Search

Your search keyword '"Lorraine Malkowitz"' showing total 40 results
Start Over Author "Lorraine Malkowitz"
40 results on '"Lorraine Malkowitz"'

1. Drosophila Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

Author

Raechel Harnoto, Morgan C. Anderson, Amy Z. Xu, Heather Hedeen, Arnaldo J. Santiago-Sanabria, Brandy L. Hammond, Kenneth Saville, Ross D. Kooienga, Christopher Chesley, Robert W. Morris, Aubree T. Gillis, Brittney Offenbacker, Katherine C. Palozola, Trisha Tomkins, Nicole Yu, Matthew Kwong, Megan E. Aldrup, Jordan E. Kus, Chelsey Friedrichs, Kenneth Stapleton, Carly E. Pelchen, Norma Chamma, Joshua F. Machone, Danielle Kulich, Andre Kennedy, Matt J. Crowley, Daniel Broomfield, Adeola Adebayo, Nicolas Ragland, Shady Messiah, Jonathan Misch, Meghan B. Rooney, Eva N. Rubio-Marrero, Will Sherrill, Joyce Stamm, Rachel R. Leads, Lindsey Shantzer, Alexis J. Scott, Andrew W. Waggoner, Kristen M. Cooper, Adam Haberman, Carmen A. Watchinski, Marcos A. Perez, Lisa Kadlec, Kiara N. Medina-Ortega, Kayla Chapman, Cheryl Bailey, Nicholas Fazzio, Insun Chong, Lasse Schmidt, Darla M. Balthaser, Megan DeShetler, Jien Shim, Anna Rogers, Chris Uitvlugt, Bryan Yarrington, Ruth A. Howe, Andrea Ochoa, Gregory J. Mullen, Young Lu Kim, Olivia L Knowles, Kevin M. Levine, Matthew M. Villerot, Thomas J. Rose, Jonathan E. Smith, Sukhjit Kaur, Roshni Patel, Olivia Plante, Tenzin Choeying, Jennifer R. Ramthun, Tiffany Y. Y. Choi, Michael Rahimi, Guzal Khayrullina, Lauren R. Boudreaux, James E. J. Bedard, Brian A. Dow, Christopher A. Louie, Kenneth S. Smith, Joannee Zumkehr, Marcus Gostelow, Melissa A. Tache, Tiffany Dai, Joan D. Zambrana-Burgos, Lauren R. Meyer, Carter Brown, Adam Brown, Travis Lamb, Carissa Belella, Hannah Gilman, David DuPuis, Ramón E. Rivera-Vicéns, Priyanka Naik, Anna L. Shipman, Jad El-Adaimi, Eric Spencer, Jonathan D. Marra, Melissa D. Patao, Sharon Ibarra, Jiayu Zhang, Ashley Vetor, Bobbi Botsford, Jenifer Winters, Nelson A. Valentín-Feliciano, Lauren M. Robinson, Christopher R. Macchi, Jennifer Hernández-Muñiz, E. Gloria C. Regisford, Jaelyn L. Johnson, Cory M. Dauphin, Tezin A. Walji, Matthew A. Zaborowicz, Stacey Winkler, Shannon M. Lowell, Marly R. McCracken, Andrew Adams, Lindsay A. Spaeder, Matthew W. Wolski, Adrese Kandahari, Fabiola Robles-Juarbe, Bryce A. Turner, Ángel L. Laboy-Corales, David T. Watson, Elaine J. Durchholz, Vanessa Rodriguez, Emily J. Teepe, Alaina C. Conturso, Eric Nyabeta Onsarigo, Tijana Martinov, Rohit Venkat, Charles R. Hauser, Priya Srikanth, Marwan Ibrahem, Karl E. Smith, Jessica M. Tucci, Ethan J. Brock, Aparna Sreenivasan, Jasmine Hales, Brianna K. Barnard, Andrew P. Stein, Jessica G. Thomas, Mallory Perella, Lorraine Rodriguez-Bonilla, Shekerah Primus, Zachary D. Moore, Caitlin M. Ament, Amber N. Hare, Brad Pamnani, Eugenia A. Soliterman, Christina Paluskievicz, Yashira M. Valentín-Feliciano, Alexandra K. Eckardt, Anya Goodman, Joseph W. Noynaert, Ashlee G. Johnson, Tyneshia C. P. Henry, Camille D. Ratliff, Ian O. Chase, Michel A. Conn, Jessica Koehler, Daniela Martiniuc, Allison J. Schepers, Megan B. Vylonis, Chrystel Dol, William Dirkes, Michelle S. Rivera-Llovet, Susana Rodríguez-Santiago, Heather L. Eisler, Mary L. Preuss, Daymon Peterson, Martin G. Burg, Aaditya Khatri, John R. Woytanowski, Holly Schiedermayer, Dara Cohn, Leah E Waldman, William M. Morris, Sharon C. Ehret, Marianna Defendini-Ávila, Jessica Fese, Suzette M. Arias-Mejias, Anna Kammrath, William D. Barshop, Edwin G. Ramírez-Aponte, Luis A. Jimenez, Carolina Marques dos Santos Vieira, Cody D. Kern, Francheska M. Delgado-Peraza, Tiffany Wan, Janice L. Krumm, Osagie Ighile, Eric D. Sassu, Jess M. Darusz, Laura Rodela, Daniel S. Nicolas, Shubha Govind, Mary Miller, Joseph E Marcus, Jason Pollack, Rostislav Castillo, Daniel Coomes, Matthew J. Borr, Diana Pérez-Afanador, Lucas A. Watson, Hannah C. Koaches, Amber Quintana, Faith H. Kung, Cameron B. Harris, Bridget M. Janssen, Cristina Zambrana-Echevarría, Jennifer K. Jones, Ian Dobbe, Benjamin M. Lewis, Lena N. Lupey, Julia A. Hilbrands, Cristina Montero Diez, Jorge L. Santiago-Ortiz, Dustin S. Woyski, Sandy D. Mach, Joseph Perez-Otero, Karim A. Sharif, Carlos Mendoza, John D. Fitzgibbons, Nelson H. Knudsen, Christy MacKinnon, Hayley M. Faber, Kwabea Agbley, Michelle Heslop, Olivia Cyrankowski, Priscilla Rodriguez, Melissa Jones, Jean M. Strelitz, Ryan A. Grove, Rachel A Greenstein, Michael Murillo, Elizabeth Greiner-Sosanko, Ciani Jean Sparks, Darryl McFarland, Franca G. Rossi, Heran Gebreyesus, Chris Kay, Danielle Ladzekpo, Chris Harward, Jordan S. Christie, Consuelo J. Alvarez, Elaine V. Morlock, Geoff Scott, Kelsey Hockenberger, Sepo Musokotwane, Adam Fearnow, Lauren J. Keny, Alaina J. Grantham, Evangelina Reza, Mike Colgan, Melanie K. Regan, Stephanie J. Potocny, Sasha L. Dorsett, Tara Skorupa, Valerie M. Gónzalez-Pérez, Vinayak S. Nikam, Anne C. Meier, Varun Sundaram, Helen B. Rankin, Andrew B. Nylander, Mariela Gines-Rosario, Laurell MacMillian, Jeannette M. Osterloh, Robert H. Allen, Melanie A. Smith, Sarah J. Spencer, Cheri M. Ackerman, Jeffrey L. Poet, Amanda J. Hay, Isaac O. Armistead, Laura K. Reed, Don W. Paetkau, Bib Yang, Enid M. Quintana-Torres, Kathryn L. Golden, Lauren A. DiLorenzo, Alen Ramic, Mark T. LeBlanc, Carl J. Minniti, Robert J. Bailey, Kristen M. Thomsen, Ashley L. Adams, Chad A. Koplinsky, Eliezer O. Perez-Colomba, Nicole A. Howey, Katie A. TerMeer, Stephanie Intriago, Christina N. Kufel, Mary Waters, Bo Liu, Thomas J. Bahr, Ashley R. Miller, Claire Pattison, Morgan R. Light, Amy T. Hark, Jennifer S. Doty, Catherine M. Mageeney, Adam J. Ronk, Nadezhda Fefelova, Andrew R. Armstrong, Maida Chen, Elizabeth Macias, Kim M. Chau, Paul Bilinski, Trevor G. Floyd, Cassidy T. Lee, Jenna C. Tenney, Bob Gardner, Patricia Ortiz-Ortiz, Elizabeth S. Jewell, Gabi Lucas, Brandon Lee, Jenifer N. Jarrell, Jimmy Hsiang-Chun Chang, Lorraine Malkowitz, Ulises Marrero-Llerena, Gabriel Stancu, Matthew R. Unzicker, Andrea P. Burgos-Bula, Michelle L. Miller, Elisandra Rivera, Kate Bagaeva, Jessica W. Polk, Jordan E. Carney, Maureen Corrielus, Jana Nietmann, Jeff Howenstein, Elizabeth Kiernan, Sabya A. Rauf, Brandon M. Katz, Elizabeth C. Nordman, Devon Shallman, Eric M. Clark, Lenin Lopez, Karen J. Kraftmann, Leslie Guadron, Julia Kuhn, Allison R. Schneiter, Satish C. Bhalla, Emily J. Howell, Blair Undem, Jeffrey S. Thompson, Arelys Flores-Vazquez, John Kiley, Cody M. Morrow, Joseline Serrano-González, John Mark Knepper, Christopher Beck, Calise Debow, Anna L. Smith, Angelica Garcia, Shelbi Christgen, Shadie Emiah, Tammy Mazur, Rachel E. VanDyken, Frank R. Soto delValle, Zachary Nichols, William R. Kennedy, Ameer Zidan, Douglas A. Herrick, Thomas Q. Xu, Elizabeth Shoop, Jessica A. Kampmeier, John M. Kerber, Caitlin Pozmanter, Emily L. Hong, Frederic J. Deuschle, Allyson B. Rivard, William Neutzling, Joseph V. Moran, Benjamin K. Johnson, Jacob Jipp, Shannon R. McCartha, Abby Vrable, Z. Goodwin, Suchita Rastogi, Alyssa M. Newman, Lionel Ortiz-Fuentes, Arjun A. Anilkumar, Bryan M. Hennessy, Hui-Min Chung, Katie L. Goeller, Carlos E. Santos-Ramos, Adam Dillman, Christine D. Wilson, Sarah J. Peacock, Andrew J. Kim, Carol I. Morales-Caraballo, Briana Brinkley, Justin Alldredge, Rebecca Krock, Kristen C. Davis, David Dunbar, Joshua L. Manghelli, Erica K. Earl, Katherine Gavinski, Sheryl T. Smith, Portia Mason, Lindsay J. Hoogenboom, Jessen T. Havill, Sonya G. Méndez-Castellanos, Darrin T. Schultz, Katherine J. Faber, Allison O’Rouke, Emily G. Miller, Yara Ashrawi, Curtiss E. Lane, Saryleine Ortiz-DeChoudens, Michael W. Sandusky, Andrew Montgomery, Rita Kabaso, Todd Aronhalt, Jonathan D. Foust, Jorge Ruiz, Eric Helmreich, Todd T. Eckdahl, Charlotte Lea, Kevin Coulson, Kristin M. French, Kate A. Woodard, Brandon J. Burkhart, Kylie McNeil, Curtis R. Edwards, Jimmy Ma, Darcie D. Elder, Tia DiTommaso, Nicholaus Monsma, Sarah A. Jelgerhuis, Stephanie J. Adams, Nichole Rigby, Heather L. Holderness, Charlotte Williams, Megan Donegan, Taylor S. Harding, Javier O. Martinez-Rodriguez, Sandeep Venkataram, Tiffany Wong, Anika Toorie, Jenny L. Rose, Ashley S. Brown, Sarah A. Popelka, Matthew Williams, Julie Bryant, Sarah C. R. Elgin, Sonali Kumar, Joshua Burkhardt, William J. Puetz, Erica L. Alvendia, Richard A. Tumminello, Kesley Parry, Joshua R. Smith, Ashley F. Custer, Carlos E. Ortiz, Yedda Li, April E. Bednarski, Simon Ng, Max Mandelbaum, Arlene J. Hoogewerf, Chelsea A. Walker, Ryan S. Lee, Jeannette Wong, Isabella Theresa Felzer-Kim, Harrison Friedman, Megan Bourland, Luis R. Colón-Cruz, Lucy Liu, Nicole C. Olson, Yi Ren, Adam P Lousararian, José M. Cruz-García, Charlie Manchee, Kyle Zoll, Kristina M. Stemler, Juliana Belén-Rodríguez, Ashley S. Timko, Jane Lopilato, England Raimey, Amy D. Melton, Joshua D. Forsyth, Christopher D. Savell, Himabindu Reddy, Alica B. Allen, Amanda Maffa, Daniel W. Cassidy, Luciann Bracero-Quiñones, Eric Lemmon, Justina R. Bartling, Bradley J. Ogden, Petros Svoronos, Mary Spratt, Lisa Sudmeier, Héctor A. Martell-Martínez, James F. Geary, Bridget J. Sessions, Christopher Campana, Kaitlyn A. Downey, Seth G. Dawson, Daniella Menillo, Casey Hanson, James M. Bellush, Justin A. Gonzales, Roy Song, Karvyn Torchon, Betsy Hoover, Michael Closser, Lacey Neufeld, Micah Shelton, Benjamin R. Does, Juan Carlos Martínez-Cruzado, Jordan S. Baumgardner, Nicole Chichearo, Mary T. Reilly, Colleen V. Kelley, Monica Yalamanchili, Dawn Lau, Abbie Morgan, Alyssa Cifelli, Milton R. Herrold, Ambreen Khan, James Messler, Kyle Westphal, James L. Kehoe, Juliana A. Wurzler, Garrett Salzman, Tracy Wang, Charlene Emerson, Lyndsey A. Reynolds, Alysha Moretti, Marita K. Abrams, Mara G. Cole, Michael B. Schultz, Samantha Cruz, Natalie Ngai, Nadia Safa, Vicente Velasquez, Ashley Townsend, Jonathan L. Crooke-Rosado, Amber M. Gygi, Ishwar S. Gill, Christopher McLaughlin, Dorianmarie Vargas-Franco, Alissa Beckett, Samantha Vue, Nadine L. Rossi, Justina Chinwong, Ryan Michael Rempe, Trip Freeburg, Amy J. Johnson, Omolara Glenn, Jade Lea Rekai, Hashini Gunasinghe, Vivienne Echendu, Marshall Strother, Morgan Baker, Christopher D. Smith, Paolo A. DaSilva, Noelle Delacruz, Tiara Tirasawasdichai, Yakov Shevin, Wilfried Guiblet, Shane M. Patao, Peterson R. Cullimore, Giancarlo F. Garbagnati, Adam E. Musick, Sarah C. Butzler, Jonathan D. Presley, Ana I. Correa-Muller, Christopher D. Shaffer, Chunguang Du, Ryan D. Mitchell, Jonathan P. Rennhack, Barbara L. Hopkins, Mary E. Shaw, Jessica E. Hill, Jeremy N. Wong, Anna Kim, Christopher B. Khoury, Julia Chapman, Amanda T. Mercer, Jessica A. Shuen, Joyce H. Lau, I.N. Falk, Sunil Rathore, Christopher J. Jones, Laura Simone Bisogno, Nighat P. Kokan, Paul Yenerall, Amber L. Price, Kelsey T. Bushhouse, Stephen L. McDaniel, Andrew P. Drake, Johnathan D. English, Sampson K. Boham, Robert A. Herbstsomer, Daniel S. Fosselman, Kevin Babilonia-Figueroa, Matthew Simon, Anne G. Rosenwald, Bryan J. Rupley, Heather Cohen, Victoria Scala, Avery B. Cromwell, Christopher E. Blunden, Yelena P. Davis, William B. Armstrong, Kristine Ostby, Joanna Haye, Lauren M. Wysocki, Lena Christiansen, Allison A. Throm, Sarah Flohr, Matthew Wawersik, Rebecca J. Cotteleer, Kristen R Ramirez, Dontae A. Jacobs, Sarah Woehlke, Gregory S. Messenger, Soham Aso, Nicole Clarke-Medley, Bryant R. Swanson, Lindsay K. Brouwer, S. Catherine Silver Key, Stephanie Zarrasola, Michael S. Salgado, Dong K. Rhee, Mai Abdelnabi, Eve VanEck, Jeremy Buhler, Sarah Kong, Turner Conrad, Jennifer Roecklein-Canfield, Marykathryn Tynon, Brian J. Maniaci, Alexa M. McDonough, Ivan G. Llavona-Cartagena, J. Devin Spencer, Todd D. Johnson, Azita Bashiri, Kimberley Ramsey, Mike Polen, Hien P Nguyen, Seantay D. Patterson, Lucia Wande, Nicholas U. Schwartz, Han Yuan, Albeliz Santiago-Colón, Joseph Medina, Samuel Thomas Crowley, Emma Shoemaker, Alex J. Feliciano-Cancela, Alexander J. Kujawski, Lillyann Asencio-Zayas, Gentry L. Pickett, Matt J. Randazzo, Erica Stagaard, Kristin M. LaForge, Gabriela A. Llaurador-Caraballo, Anastasia K. Yemelyanova, Alan Tseng, Erika E. Menyes, Julie Azarewicz, Christa Burke, Samuel I. Smith, Nazanin Ghavam, Carolina Gomez, Cameron Fick, Anthony Pinto, Lindsay Rios, Gary A Kuleck, Ashley Rich, Kayla A. Florian, Martin N. Cheramie, Yuki Kwan Wa Shum, Atlee Baker, LaJerald Augustine, Alyson Greenwell, Rasleen K. Saluja, Jason S. Macias, Wesley W. Winn, Samantha M. Schmuecker, Michelle E. M. Eisen, Pedro Benitez, Jeanette Hauke, Nora C. Goscinski, Justin R. DiAngelo, Carter T. Docking, David D. Xiong, Brittany D. Pasierb, Matt Van Camp, Yin Zheng, Nikie L. McCabe, Emily Reed, Katie Homa, Kimberly S. Kolibas, Elizabeth A. Karaska, Grace A. Dougherty, John P. Fanning, Michael Fasano, Joseph E. Sable, Robert W. Schulz, San Francisco Nguyen, Michael L. Rojas-Vargas, Kierstin L. Naylor, Emily Peoples, Jessica Neely, Lejla Cesko, Brionna D. Davis-Reyes, Roxanne Banker, Amanda K. Tilot, Jordan P. Brand, William H. Newhart, Lauriaun Johnson, Michelle M. Giddens, Nicole B. Clark, Anant Agarwalla, Thomas F. Minton, Dana W. Brooks, Amanda D. Garrett, Bethany M. Klett, Kristin M. Starkey, Antoinette E. Fafara-Thompson, Michael R. Rubin, Jonathon M. Benson, Erica Enoch, Amanda M. Damsteegt, Zackary W. Scott, Elisabeth A. Kelly, Jason M. Barnett, Wilson Leung, Luke J. Rodriguez-Giron, Krishna C. Mudumbi, Francis J. May, Nadyan M. Vargas-Barreto, Geeta Statton, José L. Torres-Castillo, Sarah Hirsch, Rachel M. Reem, Linghui Li, Deirdre Robinett, Jason Caronna, Abneris E. Rodríguez-Laboy, Samantha Lawrence, Katherine R. Reynolds, Corinne Weeks, Allison M. Sterling, Chun Leung Ng, Roman E. Ramirez, Daron C. Barnard, Leming Zhou, Eric P. Spana, John A. Toth, Alvin Lu, Krizia C. Menéndez-Serrano, Jonathan M. Heckman, Ben Chlebina, Matthew C. Fadus, Helmet T. Karim, Shailly Gaur, Timothy R. Jelsema, Nicholas Keysock, Thomas J. Carr, Zach Fusco, Evan M. Verbofsky, Monal Naik, Amanda H. Flores, Kristin A. Knouse, Olga R. Kopp, Elizabeth Feenstra, Edward P. Sweeney, Christen Johnson, Justin Crawford, Damian Urick, Victor W. Mullen, Carrie A. Dunham, Gabriella A. DeMichele, Mengyang Sun, William Harrington, Jessica M. Bodenberg, Xavier A. Collado-Méndez, T. Aaron Wiles, Michelle K. Powers, Phillip J. Minnick, Lourdes N. Irizarry-González, Valeria Silva, Steven Ovu, Nik Kolba, Peter Lindbeck, Jerome M. Molleston, Ifeanyi Obiorah, David Carranza, Lauren R. Beck, Alina M. Tamayo-Figueroa, Elaine R. Mardis, Rachel N. Lippert, Ingrid T. Rivera-Pagán, Mahdi Soos, Trung T. Nguyen, Megan Martinez, Van Kim, Benjamin L. Danner, Randall J. DeJong, Melissa M. Trieu, Andrea M. Senquiz-Gonzalez, Mary Grace Schueler, Emily E. Magnuson, Lesley E. Jackson, Hendrick Pagán-Torres, Fareed Sanusi, Dana Koenig, Vidya Chandrasekaran, Chinmoy I. Bhatiya, Dongyeon Kim, Paul J. Overvoorde, Reece Watson, Jennifer Schottler, Devry Lin, Jim Youngblom, Taylor Schauder, Nigel Madden, Isabel Valdez, Thomas John Reynolds, Kelly M. Deranek, Anne A. Welker, Jackie X. White, Nicole C. Riddle, Jacob Pfeil, Aldo Heredia-Negrón, Christine Langner, Tao Jian He, Jonathan P. Mecoli, Lissett Mayorga, Scott Chiang, Rishi Singhal, Julia C. Peairs, Michael Quach, Anne M. Eime, GiNell Elliott, Meleah J. Gross, Melissa Drewry, Julia A. Emerson, Anthony K. Lambright, Isaac Appiah, Gregory M. Robertson, Nathaniel Regenold, Philip Pham, George Odisho, Alexi Archambault, Matthew Dothager, Shana M. Baldassari, Paul J. Lee, Callie R. Merry, Jesse R. Farek, Archana Tare, Srebrenka Robic, William Vernon, Tam Vuong, Bethany Grace Bonifield, Katrina Thistle, Rose M. Dowd, Noor Tazudeen, Jennifer Weaver, Manpreet Kaur, Nicole M. Caesar, Yi Zhang, Michael C. Cristostomo, Albert Tzeng, Kayla Vondy, Emily Perling, Ramiro A. Chavez, Lanor S. Horton, Matt Kroll, Levent H. Beken, Justin R. Starcher, Sam Asinof, Nathalia M. Cruz, Eunice George, Adam T. Morrow, Heather Milnthorp, Cheryl Mazzeo, Kristen R. Hatfield, Anna L. Boudoures, Ashley A. Tewilliager, Edna P. Tascón-Peñaranda, Vilma F. Huerta, Sarah Tuberty, Mallory A. Williams, Rachel E. Weber, Sarah Spencer, Emily C. Leatherman, Yuying Gosser, Steve DeFazio, Patrick Ng, Jeri Sparks, Pavan Bhat, Mindy E. Bower, Jordan E. Matthews, Cyrus E. Kuschner, Anne Bertolet, Matt Kusner, Thomas C. Giarla, Jessica Penn, Gerard P. McNeil, Mariam Meghdari, Michael J. Wolyniak, Matthew Juergens, Karla I. Velázquez-Soto, Maria Kaisler, Jeanine Schibler, Alexis Nagengast, Susan Parrish, Frances Marín-Maldonado, Shiv Mohini, Jessica King, Danny Mammo, Katherine S. Harker, Allyson P. Hawkins, Kelly Drumm, Jennifer A. Lammers, Allyson P Mallya, Ashley Bryant, Katie Weihbrecht, Pete Wendland, Gabriela V. Bernal-Vega, Nestor A. Gutierrez, Armando G. Bermudez-Capo, Luke R. Salbert, Kirk Haltaufderhyde, Michelle L. Kappes, Mary A. Smith, York Chen, Miguel Vélez-Vázquez, Brittany E. Plescher, Francis D. Beauchamp-Pérez, Alyssa Ward, Andrea N. Clary, Don Foret, Mitchell J McDonald, Mariela Colon-Vazquez, Amanda L. Blaker, Hao Yang, James Z. Liu, Austin B. Limle, Henry Huang, Luis Vilanova-Velez, Edgar Garibay, Philip J. Freda, Laura L. Mays Hoopes, Maureen S. Hammond, Marian M. Kaehler, Rebecca Shuford, Ray Sunjed, Cynthia K. Hanson, Marielle VanderVennen, Idaliz M. Martínez-Traverso, Jack Y. Yu, Spencer L. Franchi, Michael Snavely, John E. Anderson, Lainey S. Rubin, Kelly K. Jones, Stephanie F. Mel, Stacey Lytle, Danny L. Tran, Chelsea R. Barberi, Max Mian Liu, Eric A. Nollet, Sarah E. Muller, Diana Norton, John M. Braverman, Thu A. Phan, Nelson Membreno, Colin Khoshabian, John Gooch, Cassandra Kubricky, Priscila M. Rodríguez-García, Anna Wylie, Diana L. E. Johnson, Anna K. Unruh, Deborah Hammett, Jon Sarezky, Marie Brown, Carolina Riascos-Cuero, Emily J. Diekema, Emmy E. Ogawa, Miranda Chavez, Zuzana Kocsisova, Dennis Revie, Anniken M. Lydon, Peter A. Cognetti, Ashley A. Collins, Tariq Abusheikh, Erin K. Luippold, Kevin Myirski, Brian O. Rodríguez-Echevarría, Haley J. Plasman, Lara Baatenburg, Jesse Hendriksma, Christopher R. Knob, Max Semon, Cassandra Farrar, Xiao Zhu, Ali Dobbe, Marie-Isabelle B. Seydoux, Griffin Sadovsky, Shreya Prasad, Victoria Newcomb, Chad Gier, Dmitri Serjanov, Jules Wellinghoff, Maxwell T. Smith-Gee, and Alexandra H. Scoma

Subjects
Transposable element, Codon Adaptation Index, Euchromatin, Heterochromatin, transposons, evolution of heterochromatin, Investigations, Genome, Evolution, Molecular, 03 medical and health sciences, gene size, 0302 clinical medicine, melting characteristics, Species Specificity, codon bias, Genetics, Animals, Drosophila Proteins, Selection, Genetic, Codon, Molecular Biology, Genetics (clinical), 030304 developmental biology, Polytene Chromosomes, Repetitive Sequences, Nucleic Acid, Gene Rearrangement, 0303 health sciences, biology, Computational Biology, Molecular Sequence Annotation, Gene rearrangement, Exons, Genomics, biology.organism_classification, Introns, Drosophila melanogaster, Codon usage bias, DNA Transposable Elements, Drosophila, 030217 neurology & neurosurgery
Abstract

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

Published
2015

2. 11β-HSD1 inhibition reduces atherosclerosis in mice by altering proinflammatory gene expression in the vasculature

Author

Gloria C. Koo, Martin S. Springer, Lorraine Malkowitz, Douglas W. Kawka, Kang Cheng, Qi Luo, Serguei Stepaniants, Kenneth K. Wu, Irwin I. Singer, Jeffrey Yuan, Andrew S. Plump, Cheryl B. Le Grand, Jun Zhu, Milana Maletic, Samuel D. Wright, James M. Balkovec, Gloria J.-F. Ding, Sherman T. Waddell, Xia Yang, Rolf Thieringer, Kashmira Shah, Pek Yee Lum, Mingjuan Jane Luo, I-Ming Wang, and Anne Hermanowski-Vosatka

Subjects
Vasculitis, Physiology, Genes, MHC Class II, 11β hsd1, Dehydrogenase, Laser Capture Microdissection, Biology, Proinflammatory cytokine, Mice, Apolipoproteins E, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Gene expression, Genetics, medicine, Animals, Enzyme Inhibitors, Glucocorticoids, Mice, Knockout, Gene Expression Profiling, Atherosclerosis, Microarray Analysis, medicine.disease, Lipids, Gene expression profiling, Cholesterol, Gene Expression Regulation, Immunology, Etiology, Metabolic syndrome, hormones, hormone substitutes, and hormone antagonists
Abstract

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is implicated in the etiology of metabolic syndrome. We previously showed that pharmacological inhibition of 11β-HSD1 ameliorated multiple facets of metabolic syndrome and attenuated atherosclerosis in ApoE−/− mice. However, the molecular mechanism underlying the atheroprotective effect was not clear. In this study, we tested whether and how 11β-HSD1 inhibition affects vascular inflammation, a major culprit for atherosclerosis and its associated complications. ApoE−/− mice were treated with an 11β-HSD1 inhibitor for various periods of time. Plasma lipids and aortic cholesterol accumulation were quantified. Several microarray studies were carried out to examine the effect of 11β-HSD1 inhibition on gene expression in atherosclerotic tissues. Our data suggest 11β-HSD1 inhibition can directly modulate atherosclerotic plaques and attenuate atherosclerosis independently of lipid lowering effects. We identified immune response genes as the category of mRNA most significantly suppressed by 11β-HSD1 inhibition. This anti-inflammatory effect was further confirmed in plaque macrophages and smooth muscle cells procured by laser capture microdissection. These findings in the vascular wall were corroborated by reduction in circulating MCP1 levels after 11β-HSD1 inhibition. Taken together, our data suggest 11β-HSD1 inhibition regulates proinflammatory gene expression in atherosclerotic tissues of ApoE−/− mice, and this effect may contribute to the attenuation of atherosclerosis in these animals.

Published
2013
Full Text
View/download PDF

3. Expanding the Scope of HTMS Methods

Author

Yusheng Xiong, William A. LaMarr, Ming-juan Luo, Tom G. Holt, Kristian K. Jensen, Lorraine Malkowitz, Bernard K. Choi, Maxine Jonas, Can C. Ozbal, Neil S. Geoghagen, Jun Wang, Qi Luo, Xun Chen, and Claude Dufresne

Subjects
Scope (project management), Chemistry, Environmental chemistry, Biochemical engineering
Published
2011
Full Text
View/download PDF

4. Pharmacological activation and genetic manipulation of cystathionine beta-synthase alter circulating levels of homocysteine and hydrogen sulfide in mice

Author

Tom G. Holt, Qi Luo, Shuo Quan, Ming-juan Luo, Heather Zhou, Kang Cheng, Neil S. Geoghagen, Lorraine Malkowitz, M. Gerard Waters, Kristian K. Jensen, Weihua Ni, Aiwu Zhang, and Lan Jin

Subjects
Male, inorganic chemicals, S-Adenosylmethionine, congenital, hereditary, and neonatal diseases and abnormalities, Homocysteine, Cystathionine beta-Synthase, Endogeny, Adenoviridae, Mice, chemistry.chemical_compound, In vivo, Animals, Humans, Hydrogen Sulfide, Pharmacology, chemistry.chemical_classification, Methionine, biology, Chemistry, Activator (genetics), organic chemicals, nutritional and metabolic diseases, Cystathionine beta synthase, Recombinant Proteins, Enzyme assay, Enzyme Activation, Mice, Inbred C57BL, Enzyme, Biochemistry, Mutation, biology.protein, Genetic Engineering
Abstract

Hydrogen sulfide (H(2)S) is a recently discovered gasotransmitter found in mammalian tissues and blood. Treatment with H(2)S donor molecules has shown promising results in preclinical models of inflammatory and cardiovascular diseases. Augmentation of H(2)S levels thus holds promise as a novel therapeutic approach for treatment of disease in man. Cystathionine β-synthase (CBS) has been shown to catalyze H(2)S production in vitro. CBS enzyme activity is allosterically regulated by the endogenous activator S-adenosyl methionine. This mode of regulation suggests the possibility for designing a small molecule activator of CBS to enhance H(2)S production. This hypothesis, however, has not been directly tested in vivo. We show here that CBS contributes significantly to endogenous H(2)S production in mice: adenovirus mediated over expression of CBS in the liver significantly increased circulating levels of H(2)S, whereas CBS deficiency resulted in reduced levels. We demonstrate that CBS enzyme from endogenous sources can be activated by S-adenosyl methionine to a greater extent compared to recombinant enzyme, suggesting greater potential for activation than previously anticipated. Importantly, we show that circulating H(2)S levels are increased by pharmacological activation of CBS in vivo; i.e. in the presence of the endogenous activator. Together, our data demonstrate that CBS activity partially regulates endogenous H(2)S in mice, and suggest that pharmacological activation of CBS is a promising approach for enhancing endogenous production of H(2)S for the treatment of cardiovascular and other diseases.

Published
2011
Full Text
View/download PDF

5. Label-Free High-Throughput Screening via Mass Spectrometry: A Single Cystathionine Quantitative Method for Multiple Applications

Author

Kristian K. Jensen, Qi Luo, Ming-juan Luo, Neil S. Geoghagen, Yusheng Xiong, Gergely M. Makara, Claude Dufresne, William A. LaMarr, Bernard K. Choi, Lorraine Malkowitz, Can C. Ozbal, and Tom G. Holt

Subjects
Spectrometry, Mass, Electrospray Ionization, High-throughput screening, Drug Evaluation, Preclinical, Mass spectrometry, Mass Spectrometry, Cell Line, Mice, chemistry.chemical_compound, Cystathionine, Drug Discovery, Animals, Humans, Derivatization, Chromatography, High Pressure Liquid, Chromatography, Dose-Response Relationship, Drug, biology, Drug discovery, Multiple applications, Cystathionine beta synthase, Enzyme assay, Mice, Inbred C57BL, Kinetics, chemistry, Linear range, Data Interpretation, Statistical, Calibration, biology.protein, Molecular Medicine, Indicators and Reagents
Abstract

Label-free mass spectrometric (MS) technologies are particularly useful for enzyme assay design for drug discovery screens. MS permits the selective detection of enzyme substrates or products in a wide range of biological matrices without need for derivatization, labeling, or capture technologies. As part of a cardiovascular drug discovery effort aimed at finding modulators of cystathionine beta-synthase (CBS), we used the RapidFire((R)) label-free high-throughput MS (HTMS) technology to develop a high-throughput screening (HTS) assay for CBS activity. The in vitro assay used HTMS to quantify the unlabeled product of the CBS reaction, cystathionine. Cystathionine HTMS analyses were carried out with a throughput of 7 s per sample and quantitation over a linear range of 80-10,000 nM. A compound library of 25,559 samples (or 80 384-well plates) was screened as singlets using the HTMS assay in a period of 8 days. With a hit rate of 0.32%, the actives showed a 90% confirmation rate. The in vitro assay was applied to secondary screens in more complex matrices with no additional analytical development. Our results show that the HTMS method was useful for screening samples containing serum, for cell-based assays, and for liver explants. The novel extension of the in vitro analytical method, without modification, to secondary assays resulted in a significant and advantageous economy of development time for the drug discovery project.

Published
2009
Full Text
View/download PDF

6. Potent 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists: effects of fused heterocycles on antiviral activity and pharmacokinetic properties

Author

Janet Lineberger, Emilio A. Emini, Julie A. DeMartino, Dooseop Kim, Michael W. Miller, Richard J. Budhu, Karen Henry, Renee Hrin, Gwen Carver, Lorraine Malkowitz, Anthony Carella, William A. Schleif, Malcolm MacCoss, Sandra L. Gould, Joseph Kessler, Daria J. Hazuda, Sander G. Mills, Christopher L. Lynch, Liping Wang, Jeffrey J. Hale, and Martin S. Springer

Subjects
Imidazopyridine, Pyrrolidines, Receptors, CCR5, Anti-HIV Agents, Stereochemistry, Clinical Biochemistry, Administration, Oral, Pharmaceutical Science, CCR5 receptor antagonist, Biochemistry, Pyrrolidine, chemistry.chemical_compound, Heterocyclic Compounds, Drug Discovery, Side chain, Animals, Humans, Receptor, Molecular Biology, Chemistry, Organic Chemistry, Antagonist, virus diseases, Biological activity, Rats, CCR5 Receptor Antagonists, Molecular Medicine, Piperidine, HeLa Cells
Abstract

A series of 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity.

Published
2005
Full Text
View/download PDF

7. Synthesis and evaluation of CCR5 antagonists containing modified 4-piperidinyl-2-phenyl-1-(phenylsulfonylamino)-butane

Author

Renee Danzeisen, Joseph Kessler, Karen Holmes, Anthony Carella, Janet Lineberger, Martin S. Springer, Malcolm MacCoss, Daria J. Hazuda, Natalie Chen, Sander G. Mills, Julie A. DeMartino, Emilio A. Emini, William A. Schleif, Gwen Carver, Shrenik K. Shah, Ravindra N. Guthikonda, Sandra L. Gould, Michael W. Miller, and Lorraine Malkowitz

Subjects
Anti-HIV Agents, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, CCR5 receptor antagonist, Biochemistry, Chemical synthesis, Inhibitory Concentration 50, Structure-Activity Relationship, chemistry.chemical_compound, Piperidines, Drug Discovery, Moiety, Sulfones, Molecular Biology, Dose-Response Relationship, Drug, Bicyclic molecule, Organic Chemistry, Antagonist, virus diseases, Butane, In vitro, chemistry, CCR5 Receptor Antagonists, Viruses, Butanes, Molecular Medicine, Piperidine
Abstract

Synthesis of analogs containing more rigid bicyclic piperidine replacements for the 4-benzyloxycarbonyl-(ethyl)amino-piperidine moiety of the CCR5 antagonist structure, 1, is described. Although similar binding affinity to the lead was achieved with some analogs they were overall less potent anti-HIV agents suggesting that other features besides CCR5 binding are required for good anti-viral activity.

Published
2005
Full Text
View/download PDF

8. Syntheses and SAR studies of 4-(heteroarylpiperdin-1-yl-methyl)-pyrrolidin-1-yl-acetic acid antagonists of the human CCR5 chemokine receptor

Author

Karen Holmes, Emilio A. Emini, Karla L. Donnelly, Daria J. Hazuda, Sander G. Mills, Sandra L. Gould, Joseph Kessler, Malcolm MacCoss, William A. Schleif, Shrenik K. Shah, Ravindra N. Guthikonda, Janet Lineberger, Michael D. Miller, Salvatore J. Siciliano, Anthony Carella, Gwen Carver, Martin S. Springer, Kothandaraman Shankaran, and Lorraine Malkowitz

Subjects
Pyrrolidines, Anti-HIV Agents, Stereochemistry, Carboxylic acid, Clinical Biochemistry, Pharmaceutical Science, Acetates, Biochemistry, Chemical synthesis, HeLa, Structure-Activity Relationship, Chemokine receptor, Acetic acid, chemistry.chemical_compound, Piperidines, Drug Discovery, Humans, Structure–activity relationship, Binding site, Molecular Biology, chemistry.chemical_classification, Binding Sites, biology, Organic Chemistry, virus diseases, biology.organism_classification, In vitro, chemistry, CCR5 Receptor Antagonists, HIV-1, Molecular Medicine, Cell Division, HeLa Cells
Abstract

Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed.

Published
2004
Full Text
View/download PDF

9. Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 3: SAR studies on the benzylpyrazole segment

Author

Kevin T. Chapman, Jerry Di Salvo, Gloria Y. Kwei, Salvatore J. Siciliano, Dong-Ming Shen, Min Shu, Janet Lineberger, Kathy Lyons, Gwen Carver, Karen Holmes, Renee Danzeisen, Jennifer L. Loebach, Joseph Kessler, Martin S. Springer, James V. Pivnichny, Lorraine Malkowitz, Kerry A Parker, William A. Schleif, Emilio A. Emini, Daria J. Hazuda, Sander G. Mills, Sandra L. Gould, Anthony Carella, Julie A. DeMartino, and Michael D. Miller

Subjects
Anti-HIV Agents, Stereochemistry, Clinical Biochemistry, Substituent, Biological Availability, Pharmaceutical Science, CCR5 receptor antagonist, Biochemistry, Chemical synthesis, Monocytes, Structure-Activity Relationship, chemistry.chemical_compound, Dogs, Piperidines, Drug Discovery, Animals, Humans, Structure–activity relationship, Molecular Biology, Molecular Structure, Chemistry, Organic Chemistry, Rats, CCR5 Receptor Antagonists, Alkoxy group, Benzyl group, Pyrazoles, Molecular Medicine, Piperidine, Selectivity, HeLa Cells
Abstract

Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.

Published
2004
Full Text
View/download PDF

10. Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 1: Discovery and SAR study of 4-pyrazolylpiperidine side chains

Author

Min Shu, Janet Lineberger, William A. Schleif, Salvatore J. Siciliano, Renee Danzeisen, Joseph Kessler, Karen Holmes, Martin S. Springer, Julie A. DeMartino, Kevin T. Chapman, Dong-Ming Shen, Anthony Carella, Lorraine Malkowitz, Michael D. Miller, Gloria Y. Kwei, Daria J. Hazuda, Sander G. Mills, Emilio A. Emini, Gwen Carver, and Sandra L. Gould

Subjects
Anti-HIV Agents, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Pyrazole, Biochemistry, Chemical synthesis, Structure-Activity Relationship, chemistry.chemical_compound, Piperidines, Drug Discovery, Side chain, Animals, Humans, Moiety, Phenyl group, Isoxazole, Molecular Biology, Molecular Structure, Organic Chemistry, Rats, chemistry, CCR5 Receptor Antagonists, Benzyl group, Pyrazoles, Molecular Medicine, Piperidine, Cell Division, HeLa Cells
Abstract

Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.

Published
2004
Full Text
View/download PDF

11. 1,3,4 trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains

Author

Margaret A. Cascieri, Salvatore J. Siciliano, Karen Holmes, Sandra L. Gould, Kevin T. Chapman, William A. Schleif, J. J. Hale, Richard J. Budhu, Renee Danzeisen, Joseph Kessler, Anthony Carella, Julie A. DeMartino, Christopher A. Willoughby, Daria J. Hazuda, Sander G. Mills, Malcolm MacCoss, Michael W. Miller, Janet Lineberger, Emilio A. Emini, Lorraine Malkowitz, Keith G. Rosauer, Martin S. Springer, and Gwen Carver

Subjects
Pyrrolidines, Anti-HIV Agents, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, CHO Cells, CCR5 receptor antagonist, Biochemistry, Chemical synthesis, Pyrrolidine, chemistry.chemical_compound, Piperidines, In vivo, Cricetinae, Drug Discovery, Side chain, Animals, Humans, Chemokine CCL4, Molecular Biology, Organic Chemistry, Antagonist, Hydrogen Bonding, Macrophage Inflammatory Proteins, In vitro, Rats, chemistry, CCR5 Receptor Antagonists, Molecular Medicine, Piperidine, Half-Life, HeLa Cells
Abstract

A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC95=50 nM). Compound 4a also has improved PK properties relative to 1.

Published
2003
Full Text
View/download PDF

12. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 4: Synthesis of N-1 acidic functionality affording analogues with enhanced antiviral activity against HIV

Author

Emilio A. Emini, Julie A. DeMartino, Salvatore J. Siciliano, Karen Holmes, Gwen Carver, Sandra L. Gould, Kevin T. Chapman, Anthony Carella, Renee Danzeisen, Michael W. Miller, Joseph Kessler, Malcolm MacCoss, Christopher L. Lynch, Daria J. Hazuda, Sander G. Mills, Janet Lineberger, Lorraine Malkowitz, Amy Gentry, Richard J. Budhu, Jeffrey J. Hale, William A. Schleif, Margaret A. Cascieri, and Martin S. Springer

Subjects
Cell Membrane Permeability, Pyrrolidines, Chemical Phenomena, Anti-HIV Agents, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, CHO Cells, CCR5 receptor antagonist, Biochemistry, Chemical synthesis, Pyrrolidine, Structure-Activity Relationship, chemistry.chemical_compound, In vivo, Cricetinae, Drug Discovery, Animals, Humans, Structure–activity relationship, Chemokine CCL4, Molecular Biology, Chemistry, Physical, Chemistry, Chinese hamster ovary cell, Organic Chemistry, Antagonist, Macrophage Inflammatory Proteins, In vitro, Rats, CCR5 Receptor Antagonists, HIV-1, Molecular Medicine, Indicators and Reagents, HeLa Cells
Abstract

A series of alpha-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.

Published
2002
Full Text
View/download PDF

13. Combinatorial synthesis of 3-(Amidoalkyl) and 3-(Aminoalkyl)-2-arylindole derivatives: discovery of potent ligands for a variety of G-protein coupled receptors

Author

Madhumeeta J Dhar, Lorraine Malkowitz, Kevin T. Chapman, Kang Cheng, Steven M. Hutchins, Stephen G. Pacholok, Christopher A. Willoughby, Keith G. Rosauer, Gary G. Chicchi, David H. Weinberg, Sharon Sadowski, Smita Patel, and Jerry Di Salvo

Subjects
Indoles, Stereochemistry, G protein, medicine.drug_class, Clinical Biochemistry, Drug Evaluation, Preclinical, Pharmaceutical Science, Receptors, Cell Surface, Carboxamide, Ligands, Binding, Competitive, Biochemistry, Chemical synthesis, Structure-Activity Relationship, GTP-Binding Proteins, Drug Discovery, medicine, Combinatorial Chemistry Techniques, Humans, Amines, Receptor, Molecular Biology, Receptors, Tachykinin, G protein-coupled receptor, Bicyclic molecule, Chemistry, Ligand, Organic Chemistry, Amides, Receptors, Serotonin, Molecular Medicine, Receptors, Chemokine, Amine gas treating
Abstract

Preparation and screening of mixture libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors.

Published
2002
Full Text
View/download PDF

14. Combinatorial synthesis of CCR5 antagonists

Author

Anthony Carella, Kevin T. Chapman, Christopher A. Willoughby, Martin S. Springer, Lorraine Malkowitz, Janet Lineberger, Emilio A. Emini, Karen Holmes, Keith G. Rosauer, Scott C. Berk, Gwen Carver, Michael W. Miller, Silvia Degrado, Sandra L. Gould, Daria J. Hazuda, Renee Danzeisen, Joseph Kessler, and William A. Schleif

Subjects
Library design, Combinatorial Chemistry Techniques, biology, Chemistry, Chemokine receptor CCR5, Stereochemistry, Organic Chemistry, Clinical Biochemistry, Antagonist, virus diseases, Pharmaceutical Science, CCR5 receptor antagonist, Combinatorial synthesis, Biochemistry, Chemical synthesis, Structure-Activity Relationship, CCR5 Receptor Antagonists, Drug Discovery, HIV-1, biology.protein, Molecular Medicine, Structure–activity relationship, Molecular Biology
Abstract

Herein we report the preparation of a combinatorial library of compounds with potent CCR5 binding affinity. The library design was aided by SAR generated in a traditional medicinal chemistry effort. Compounds with novel combinations of subunits were discovered that have high binding affinity for the CCR5 receptor. A potent CCR5 antagonist from the library, compound 11 was found to have moderate anti-HIV-1 activity.

Published
2001
Full Text
View/download PDF

15. Discovery of human CCR5 antagonists containing hydantoins for the treatment of HIV-1 infection

Author

William A. Schleif, Karen Holmes, Julie A. DeMartino, Liping Wang, Anthony Carella, Gwen Carver, Lorraine Malkowitz, Malcolm MacCoss, Paul E. Finke, Bryan Oates, Janet Lineberger, Emilio A. Emini, Ping Chen, Renee Danzeisen, Joseph Kessler, Michael W. Miller, Martin S. Springer, Sandra L. Gould, Daria J. Hazuda, Sander G. Mills, Dooseop Kim, and Charles G. Caldwell

Subjects
Anti-HIV Agents, Chemokine receptor CCR5, Clinical Biochemistry, Human immunodeficiency virus (HIV), Pharmaceutical Science, HIV Infections, Pharmacology, medicine.disease_cause, Biochemistry, Chemical synthesis, Virus, Drug Discovery, medicine, Humans, skin and connective tissue diseases, Molecular Biology, biology, Chemistry, Hydantoins, fungi, Organic Chemistry, biology.organism_classification, In vitro, body regions, CCR5 Receptor Antagonists, Lentivirus, Benzene derivatives, HIV-1, Hydantoin derivatives, biology.protein, Molecular Medicine
Abstract

A series of hydantoin derivatives has been discovered as highly potent nonpeptide antagonists for the human CCR5 receptor. The synthesis, SAR, and biological profiles of this class of antagonists are described.

Published
2001
Full Text
View/download PDF

16. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 2: lead optimization affording selective, orally bioavailable compounds with potent Anti-HIV activity

Author

Janet Lineberger, Julie A. DeMartino, Salvatore J. Siciliano, Paul E. Finke, Richard J. Budhu, Gwen Carver, Malcolm MacCoss, Karen Holmes, Jeffrey J. Hale, Renee Danzeisen, Sandra L. Gould, Joseph Kessler, Bryan Oates, Edward Holson, William A. Schleif, Anthony Carella, Emilio A. Emini, Daria J. Hazuda, Sander G. Mills, Lorraine Malkowitz, Michael W. Miller, and Martin S. Springer

Subjects
Pyrrolidines, Anti-HIV Agents, Stereochemistry, Clinical Biochemistry, Nitro compound, Administration, Oral, Biological Availability, Pharmaceutical Science, CHO Cells, Microbial Sensitivity Tests, CCR5 receptor antagonist, Biochemistry, Chemical synthesis, Pyrrolidine, Structure-Activity Relationship, chemistry.chemical_compound, Oral administration, Cricetinae, Drug Discovery, Animals, Humans, Molecular Biology, chemistry.chemical_classification, biology, Organic Chemistry, Antagonist, HIV, virus diseases, biology.organism_classification, In vitro, chemistry, CCR5 Receptor Antagonists, Lentivirus, Molecular Medicine, HeLa Cells
Abstract

Investigations of the structure-activity relationships of 1,3,4-trisubstituted pyrrolidine human CCR5 receptor antagonists afforded orally bioavailable compounds with the ability to inhibit HIV replication in vitro.

Published
2001
Full Text
View/download PDF

17. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4: synthesis and structure–Activity relationships for 1-[N-(Methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidin-1-yl)butanes

Author

Paul E. Finke, Emilio A. Emini, Sandra L. Gould, Michael W. Miller, Martin S. Springer, Lorraine Malkowitz, Anthony Carella, Karen Holmes, Julie A. DeMartino, Gwen Carver, Daria J. Hazuda, Sander G. Mills, Renee Danzeisen, Joseph Kessler, William A. Schleif, Malcolm MacCoss, Janet Lineberger, and Bryan Oates

Subjects
Anti-HIV Agents, Neutrophils, Stereochemistry, Clinical Biochemistry, Drug Evaluation, Preclinical, Pharmaceutical Science, CCR5 receptor antagonist, Biochemistry, Chemical synthesis, Inhibitory Concentration 50, Structure-Activity Relationship, chemistry.chemical_compound, Piperidines, Cricetinae, Drug Discovery, Animals, Humans, Structure–activity relationship, Molecular Biology, IC50, Cells, Cultured, Alkyl, chemistry.chemical_classification, Organic Chemistry, Antagonist, chemistry, Drug Design, CCR5 Receptor Antagonists, Butanes, HIV-1, Molecular Medicine, Piperidine, Selectivity
Abstract

(2S)-2-(3-Chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (1b) has been identified as a potent CCR5 antagonist having an IC50=10 nM. Herein, structure-activity relationship studies of non-spiro piperidines are described, which led to the discovery of 4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidine derivatives (3-5) as potent CCR5 antagonists.

Published
2001
Full Text
View/download PDF

18. CCR5, CXCR4, and CD4 Are Clustered and Closely Apposed on Microvilli of Human Macrophages and T Cells

Author

S Scott, Sandra L. Gould, Jayne Chin, Lorraine Malkowitz, Janet Lineberger, Salvatore J. Siciliano, Julie A. DeMartino, Hollis R. Williams, Lyndon J. Mitnaul, Michael D. Miller, Jerry DiSalvo, Mary Jo Staruch, Douglas W. Kawka, Irwin I. Singer, H J Zweerink, Martin S. Springer, and Bruce L. Daugherty

Subjects
Receptors, CXCR4, Receptors, CCR5, Receptors, CCR2, T-Lymphocytes, Immunoelectron microscopy, Immunology, Integrin, Fluorescent Antibody Technique, Golgi Apparatus, HIV Antibodies, HIV Envelope Protein gp120, Microbiology, Cell Line, symbols.namesake, Chemokine receptor, Membrane Microdomains, Virology, medicine, Animals, Humans, Microscopy, Immunoelectron, Cells, Cultured, Microvilli, biology, Macrophages, Secretory Vesicles, Chemotaxis, Cell migration, Immunogold labelling, Golgi apparatus, Microvillus, Virus-Cell Interactions, Cell biology, medicine.anatomical_structure, Insect Science, CD4 Antigens, HIV-1, Microscopy, Electron, Scanning, symbols, biology.protein, Thermodynamics, Receptors, Chemokine, Rabbits
Abstract

The chemokine receptors CCR5 and CXCR4 act synergistically with CD4 in an ordered multistep mechanism to allow the binding and entry of human immunodeficiency virus type 1 (HIV-1). The efficiency of such a coordinated mechanism depends on the spatial distribution of the participating molecules on the cell surface. Immunoelectron microscopy was performed to address the subcellular localization of the chemokine receptors and CD4 at high resolution. Cells were fixed, cryoprocessed, and frozen; 80-nm cryosections were double labeled with combinations of CCR5, CXCR4, and CD4 antibodies and then stained with immunogold. Surprisingly, CCR5, CXCR4, and CD4 were found predominantly on microvilli and appeared to form homogeneous microclusters in all cell types examined, including macrophages and T cells. Further, while mixed microclusters were not observed, homogeneous microclusters of CD4 and the chemokine receptors were frequently separated by distances less than the diameter of an HIV-1 virion. Such distributions are likely to facilitate cooperative interactions with HIV-1 during virus adsorption to and penetration of human leukocytes and have significant implications for development of therapeutically useful inhibitors of the entry process. Although the mechanism underlying clustering is not understood, clusters were observed in smalltrans-Golgi vesicles, implying that they were organized shortly after synthesis and well before insertion into the cellular membrane. Chemokine receptors normally act as sensors, detecting concentration gradients of their ligands and thus providing directional information for cellular migration during both normal homeostasis and inflammatory responses. Localization of these sensors on the microvilli should enable more precise monitoring of their environment, improving efficiency of the chemotactic process. Moreover, since selectins, some integrins, and actin are also located on or in the microvillus, this organelle has many of the major elements required for chemotaxis.

Published
2001
Full Text
View/download PDF

19. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 2: structure–activity relationships for substituted 2-aryl-1-[ N -(methyl)- N -(phenylsulfonyl)amino]-4-(piperidin-1-yl)butanes

Author

Karen Holmes, Michael W. Miller, Malcolm MacCoss, Lorraine Malkowitz, Renee Danzeisen, Gwen Carver, Salvatore J. Siciliano, Martin S. Springer, Joseph Kessler, Daria J. Hazuda, Sander G. Mills, Julie A. DeMartino, Bruce L. Daugherty, Janet Lineberger, William A. Schleif, Emilio A. Emini, Bryan Oates, Anthony Carella, Laura C. Meurer, Sandra L. Gould, and Paul E. Finke

Subjects
Anti hiv 1, Receptors, CCR5, Anti-HIV Agents, Stereochemistry, Chemokine receptor CCR5, Clinical Biochemistry, Pharmaceutical Science, CHO Cells, CCR5 receptor antagonist, Butylamines, Transfection, Biochemistry, Inhibitory Concentration 50, Structure-Activity Relationship, chemistry.chemical_compound, Piperidines, Cricetinae, Drug Discovery, Animals, Combinatorial Chemistry Techniques, Humans, Chemokine CCL4, Molecular Biology, IC50, Sulfonamides, biology, Aryl, Organic Chemistry, Butane, Macrophage Inflammatory Proteins, chemistry, CCR5 Receptor Antagonists, Butanes, Lead structure, biology.protein, Molecular Medicine, Antagonism, Protein Binding
Abstract

(2S)-2-(3,4-Dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (3) has been identified as a potent CCR5 antagonist lead structure having an IC50 = 35 nM. Herein, we describe the structure-activity relationship studies directed toward the requirement for and optimization of the C-2 phenyl fragment. The phenyl was found to be important for CCR5 antagonism and substitution was limited to small moieties at the 3-position (13 and 16: X= H, 3-F, 3-Cl, 3-Me).

Published
2001
Full Text
View/download PDF

20. A nonpeptidic agonist ligand of the human C5a receptor: Synthesis, binding affinity optimization and functional characterization

Author

Eric E. Allen, C J Molineaux, Lorraine Malkowitz, Debra Ondeyka, Salvatore J. Siciliano, Nathan B. Mantlo, Bing Li, Ralph A. Rivero, William J. Greenlee, S. E. De Laszlo, and Martin S. Springer

Subjects
Agonist, medicine.drug_class, Stereochemistry, Chemistry, Ligand binding assay, Organic Chemistry, Clinical Biochemistry, Pharmaceutical Science, hemic and immune systems, chemical and pharmacologic phenomena, Carboxamide, Ligand (biochemistry), Biochemistry, Chemical synthesis, C5a receptor, Drug Discovery, medicine, Functional selectivity, Molecular Medicine, Molecular Biology, Function (biology)
Abstract

The structural optimization for binding affinity and attempted modification of agonist function of a nonpeptide ligand of the human C5a receptor is described.

Published
1997
Full Text
View/download PDF

21. Cloning, expression, and characterization of the human eosinophil eotaxin receptor

Author

A Sirotina, Lorraine Malkowitz, Bruce L. Daugherty, Marty S. Springer, S J Siciliano, and Julie A. DeMartino

Subjects
Eotaxin, Chemokine CCL11, Monocyte Chemoattractant Proteins, Chemotactic Factors, Eosinophil, Receptors, CCR3, Immunology, CCR3, Molecular Sequence Data, Transfection, Polymerase Chain Reaction, Allergic inflammation, Cell Line, Chemokine receptor, Tumor Cells, Cultured, Immunology and Allergy, Humans, Amino Acid Sequence, Chemokine CCL7, Cloning, Molecular, Receptors, Cytokine, Chemokine CCL5, DNA Primers, Base Sequence, Sequence Homology, Amino Acid, Chemistry, Articles, respiratory system, Beta Chemokine, Molecular biology, Recombinant Proteins, Eosinophils, Kinetics, Chemokines, CC, Cytokines, Calcium, Receptors, Chemokine, Chemokines, CC chemokine receptors, CCL24
Abstract

Although there is a mounting body of evidence that eosinophils are recruited to sites of allergic inflammation by a number of beta-chemokines, particularly eotaxin and RANTES, the receptor that mediates these actions has not been identified. We have now cloned a G protein-coupled receptor, CC CKR3, from human eosinophils which, when stably expressed in AML14.3D10 cells bound eotaxin, MCP-3 and RANTES with Kds of 0.1, 2.7 and 3.1 nM, respectively. CC CKR3 also bound MCP-1 with lower affinity, but did not bind MIP-1 alpha or MIP-1 beta. Eotaxin, RANTES, and to a lessor extent MCP-3, but not the other chemokines, activated CC CKR3 as determined by their ability to stimulate a Ca(2+) -flux. Competition binding studies on primary eosinophils gave binding affinities for the different chemokines which were indistinguishable from those measured with CC CKR3. Since CC CKR3 is prominently expressed in eosinophils we conclude that CC CKR3 is the eosinophil eotaxin receptor. Eosinophils also express a much lower level of a second chemokine receptor, CC CKR1, which appears to be responsible for the effects of MIP-1 alpha.

Published
1996

22. ChemInform Abstract: A Nonpeptidic Agonist Ligand of the Human C5a Receptor: Synthesis, Binding Affinity Optimization and Functional Characterization

Author

S. E. De Laszlo, C J Molineaux, Martin S. Springer, Salvatore J. Siciliano, Nathan B. Mantlo, Lorraine Malkowitz, Debra Ondeyka, William J. Greenlee, Eric E. Allen, Ralph A. Rivero, and Bing Li

Subjects
Agonist, medicine.drug_class, Stereochemistry, Chemistry, medicine, hemic and immune systems, chemical and pharmacologic phenomena, General Medicine, Ligand (biochemistry), Function (biology), C5a receptor
Abstract

The structural optimization for binding affinity and attempted modification of agonist function of a nonpeptide ligand of the human C5a receptor is described.

Published
2010
Full Text
View/download PDF

23. ChemInform Abstract: 1,3,4-Trisubstituted Pyrrolidine CCR5 Receptor Antagonists. Part 1. Discovery of the Pyrrolidine Scaffold and Determination of Its Stereochemical Requirements

Author

Julie A. DeMartino, Lorraine Malkowitz, Sander G. Mills, Jeffrey J. Hale, Salvatore J. Siciliano, Sandra L. Gould, Martin S. Springer, Malcolm MacCoss, and Richard J. Budhu

Subjects
Scaffold, biology, Chemokine receptor CCR5, Stereochemistry, Chinese hamster ovary cell, Cell, Regioselectivity, General Medicine, CCR5 receptor antagonist, Pyrrolidine, chemistry.chemical_compound, medicine.anatomical_structure, Membrane, chemistry, medicine, biology.protein
Abstract

A series of 1,3,4-trisubstituted pyrrolidines was discovered to have the ability to displace [ 125 I]-MIP-1α from the CCR5 receptor expressed on Chinese hamster ovary (CHO) cell membranes. CCR5 activity was found to be dependent on the regiochemistry and the absolute stereochemistry of the pyrrolidine.

Published
2010
Full Text
View/download PDF

24. Isolation and structure of antagonists of chemokine receptor (CCR5)

Author

Robert P. Borris, Jon D. Polishook, Sheo B. Singh, Kithsiri Herath, Hiranthi Jayasuriya, Ziqiang Guan, Lorraine Malkowitz, S J Siciliano, John G. Ondeyka, Marty S Springer, Anne W. Dombrowski, Gerald F. Bills, S. N. Tiwari, Manuel Sanchez, and Dennis W. Stevenson

Subjects
Sesterterpenes, Chemokine receptor CCR5, Stereochemistry, medicine.drug_class, Pyridines, Pharmaceutical Science, CCR5 receptor antagonist, HIV Envelope Protein gp120, Analytical Chemistry, chemistry.chemical_compound, Inhibitory Concentration 50, Lauraceae, Drug Discovery, medicine, Humans, Receptor, Mode of action, Pharmacology, Natural product, biology, Molecular Structure, Terpenes, Organic Chemistry, Fungi, Receptor antagonist, biology.organism_classification, Small molecule, Cytochalasins, Complementary and alternative medicine, chemistry, Biochemistry, CCR5 Receptor Antagonists, CD4 Antigens, biology.protein, Aniba, Molecular Medicine
Abstract

Human CCR5 is a G-coupled receptor that binds to the envelope protein gp120 and CD4 and mediates the HIV-1 viral entry into the cells. The blockade of this binding by a small molecule receptor antagonist could lead to a new mode of action agent for HIV-1 and AIDS. Screening of natural product extracts led to the identification of anibamine (1), a novel pyridine quaternary alkaloid as a TFA salt, from Aniba sp.; ophiobolin C from fermentation extracts of fungi Mollisia sp.; and 19,20-epoxycytochalasin Q from Xylaria sp. Formation of the TFA salt of anibamine is plausibly an artifact of the isolation. The identity of the natural counterion is unknown. Anibamine.TFA competed for the binding of 125I-gp120 to human CCR5 with an IC50 of 1 microM. Ophiobolin C and 19,20-epoxycytochalasin Q exhibited binding IC50) values of 40 and 60 microM, respectively.

Published
2004

25. Syntheses and biological evaluation of 5-(piperidin-1-yl)-3-phenyl-pentylsulfones as CCR5 antagonists

Author

Karen Holmes, Charles G. Caldwell, Salvatore J. Siciliano, Renee Danzeisen, Joseph Kessler, Julie A. DeMartino, Martin S. Springer, Ping Chen, William A. Schleif, Shrenik K. Shah, Michael D. Miller, Daria J. Hazuda, Sander G. Mills, Gwen Carver, Kothandaraman Shankaran, Malcolm MacCoss, Janet Lineberger, Lorraine Malkowitz, Karla L. Donnelly, Anthony Carella, Sandra L. Gould, Emilio A. Emini, Paul E. Finke, Gloria Kwei, and Bryan Oates

Subjects
Receptors, CCR5, Stereochemistry, Anti-HIV Agents, Clinical Biochemistry, Human immunodeficiency virus (HIV), Pharmaceutical Science, medicine.disease_cause, Biochemistry, Chemical synthesis, Sulfone, Cell Line, chemistry.chemical_compound, Inhibitory Concentration 50, Structure-Activity Relationship, Piperidines, Drug Discovery, medicine, Humans, Sulfones, Molecular Biology, Biological evaluation, Binding Sites, Chemistry, Organic Chemistry, virus diseases, Stereoisomerism, Cd4 receptors, In vitro, Drug Design, Benzene derivatives, CCR5 Receptor Antagonists, CD4 Antigens, Molecular Medicine, Piperidine
Abstract

Cellular proliferation of HIV-1 requires the cooperative assistance of both the CCR5 and CD4 receptors. Our medicinal chemistry efforts in this area have resulted in the identification of N-alkyl piperidine sulfones as CCR5 antagonists. These compounds display potent binding and show antiviral properties in HIV-1 spread cell-based assays.

Published
2004

26. Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 2: Discovery of potent, selective, and orally bioavailable compounds

Author

Salvatore J. Siciliano, Karen Holmes, Jeffrey J. Hale, Dong-Ming Shen, Shrenik K. Shah, Christopher A. Willoughby, Michael D. Miller, Anthony Carella, Lorraine Malkowitz, Julie A. DeMartino, Kathy Lyons, Min Shu, James V. Pivnichny, Emilio A. Emini, William A. Schleif, Gloria Y. Kwei, Martin S. Springer, Gwen Carver, Renee Danzeisen, Sandra L. Gould, Joseph Kessler, Daria J. Hazuda, Sander G. Mills, Christopher L. Lynch, Janet Lineberger, and Kevin T. Chapman

Subjects
Anti-HIV Agents, Clinical Biochemistry, Pharmaceutical Science, Administration, Oral, Biological Availability, Pyrazole, Acetates, Biochemistry, Chemical synthesis, Pyrrolidine, Monocytes, chemistry.chemical_compound, Acetic acid, Structure-Activity Relationship, Dogs, Piperidines, Pyrazole Compound, Drug Discovery, Organic chemistry, Animals, Humans, Molecular Biology, Molecular Structure, Organic Chemistry, Combinatorial chemistry, Macaca mulatta, Rats, chemistry, CCR5 Receptor Antagonists, Molecular Medicine, Pyrazoles, Piperidine, Trifluoromethanesulfonate, Isopropyl, HeLa Cells
Abstract

Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered.

Published
2003

27. CCR5 antagonists: 3-(pyrrolidin-1-yl)propionic acid analogues with potent anti-HIV activity

Author

Kevin T. Chapman, Karen Holmes, Salvatore J. Siciliano, Gwen Carver, Michael W. Miller, Julie A. DeMartino, Malcolm MacCoss, Margaret A. Cascieri, Richard J. Budhu, Emilio A. Emini, Paul E. Finke, Janet Lineberger, Daria J. Hazuda, Sander G. Mills, Lorraine Malkowitz, Anthony Carella, Dong-Ming Shen, Jeffrey J. Hale, Sandra L. Gould, Amy L. Gentry, Christopher L. Lynch, Charles G. Caldwell, Martin S. Springer, William A. Schleif, Renee Danzeisen, and Joseph Kessler

Subjects
Anti hiv activity, Pyrrolidines, biology, Stereochemistry, Chemokine receptor CCR5, Anti-HIV Agents, Organic Chemistry, Biological Availability, Biochemistry, chemistry.chemical_compound, Pharmacokinetics, chemistry, CCR5 Receptor Antagonists, biology.protein, Physical and Theoretical Chemistry, Propionates, Cyclopentane
Abstract

[reaction: see text] A novel approach to alpha,alpha-disubstituted-beta-amino acids (beta(2,2)-amino acids) was employed in the synthesis of a series of 3-(pyrrolidin-1-yl)propionic acids possessing high affinity for the CCR5 receptor and potent anti-HIV activity. The rat pharmacokinetics for these new analogues featured higher bioavailabilities and lower rates of clearance as compared to cyclopentane 1.

Published
2003

28. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains

Author

Christopher L. Lynch, Janet Lineberger, Julie A. DeMartino, Ping Chen, Scott C. Berk, Margaret A. Cascieri, Gwen Carver, Michael W. Miller, Edward J. Holson, Liya Chen, Martin S. Springer, Sandra L. Gould, Kevin T. Chapman, Jeffrey J. Hale, Karen Holmes, Renee Danzeisen, William A. Schleif, Malcolm MacCoss, Joseph Kessler, Richard J. Budhu, Anthony Carella, Charles G. Caldwell, Christopher A. Willoughby, Lorraine Malkowitz, Daria J. Hazuda, Sander G. Mills, Salvatore J. Siciliano, Emilio A. Emini, Amy Gentry, and Keith G. Rosauer

Subjects
Pyrrolidines, Stereochemistry, Anti-HIV Agents, Metabolic Clearance Rate, Clinical Biochemistry, Pharmaceutical Science, CCR5 receptor antagonist, Biochemistry, Chemical synthesis, Pyrrolidine, Sulfone, chemistry.chemical_compound, Radioligand Assay, Structure-Activity Relationship, Dogs, Piperidines, Drug Discovery, Tumor Cells, Cultured, Moiety, Animals, Humans, Methylene, Molecular Biology, Organic Chemistry, Antagonist, Macaca mulatta, Rats, chemistry, CCR5 Receptor Antagonists, Leukocytes, Mononuclear, Molecular Medicine, Piperidine, Half-Life
Abstract

The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.

Published
2002

29. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 3: polar functionality and its effect on anti-HIV-1 activity

Author

Gwen Carver, Lorraine Malkowitz, Michael W. Miller, Karen Holmes, Salvatore J. Siciliano, Jeffrey J. Hale, Daria J. Hazuda, Martin S. Springer, Sander G. Mills, Julie A. DeMartino, Renee Danzeisen, Joseph Kessler, Malcolm MacCoss, Janet Lineberger, William A. Schleif, Richard J. Budhu, Sandra L. Gould, Anthony Carella, and Emilio A. Emini

Subjects
Anti hiv 1, Calcium Channels, L-Type, Chemical Phenomena, Receptors, CCR5, Stereochemistry, Anti-HIV Agents, Clinical Biochemistry, Pharmaceutical Science, CCR5 receptor antagonist, CHO Cells, Biochemistry, Chemical synthesis, Pyrrolidine, chemistry.chemical_compound, Structure-Activity Relationship, Cricetinae, Drug Discovery, Animals, Humans, Chemokine CCL4, Molecular Biology, Chemistry, Chemistry, Physical, Calcium channel, Organic Chemistry, Antagonist, virus diseases, Macrophage Inflammatory Proteins, In vitro, Rats, CCR5 Receptor Antagonists, HIV-1, Molecular Medicine, Selectivity, Half-Life, HeLa Cells
Abstract

Incorporation of acidic functional groups into a lead CCR5 antagonist identified from a targeted combinatorial library resulted in compounds with enhanced anti-HIV-1 activity and attenuated L-type calcium channel affinity.

Published
2002

30. CCR5 antagonists: bicyclic isoxazolidines as conformationally constrained N-1-substituted pyrrolidines

Author

Anthony Carella, Martin S. Springer, Margaret A. Cascieri, Emilio A. Emini, Lorraine Malkowitz, Malcolm MacCoss, Janet Lineberger, Sandra L. Gould, Karen Holmes, Daria J. Hazuda, Sander G. Mills, George A. Doss, Julie A. DeMartino, Michael W. Miller, Salvatore J. Siciliano, Renee Danzeisen, Joseph Kessler, Christopher L. Lynch, Gwen Carver, Amy Gentry, William A. Schleif, and Jeffrey J. Hale

Subjects
Pyrrolidines, Chemokine receptor CCR5, Stereochemistry, Anti-HIV Agents, Clinical Biochemistry, Human immunodeficiency virus (HIV), Molecular Conformation, Pharmaceutical Science, Microbial Sensitivity Tests, medicine.disease_cause, Biochemistry, Chemical synthesis, Nitrone, Structure-Activity Relationship, Drug Discovery, medicine, Humans, Molecular Biology, chemistry.chemical_classification, biology, Bicyclic molecule, Organic Chemistry, virus diseases, Isoxazoles, Bridged Bicyclo Compounds, Heterocyclic, Cycloaddition, chemistry, CCR5 Receptor Antagonists, biology.protein, HIV-1, Molecular Medicine, Pharmacophore, Protein Binding
Abstract

A series of CCR5 antagonists containing bicyclic isoxazolidines was generated through a nitrone mediated cycloaddition with olefins bearing the preferred pharmacophores previously described. Potent antagonists (3 and 16) were generated with enhanced affinity for the CCR5 receptor while maintaining antiviral activity against HIV.

Published
2002

31. Design, synthesis, and SAR of heterocycle-containing antagonists of the human CCR5 receptor for the treatment of HIV-1 infection

Author

Anthony Carella, Janet Lineberger, Karen Holmes, Julie A. DeMartino, Sandra L. Gould, Liping Wang, Ping Chen, Paul E. Finke, Gwen Carver, Daria J. Hazuda, Sander G. Mills, Michael W. Miller, William A. Schleif, Martin S. Springer, Emilio A. Emini, Bryan Oates, Renee Danzeisen, Lorraine Malkowitz, Malcolm MacCoss, Joseph Kessler, Charles G. Caldwell, and Dooseop Kim

Subjects
Stereochemistry, Chemokine receptor CCR5, Anti-HIV Agents, Clinical Biochemistry, Human immunodeficiency virus (HIV), Pharmaceutical Science, Hydantoin, HIV Infections, medicine.disease_cause, Biochemistry, Chemical synthesis, chemistry.chemical_compound, Structure-Activity Relationship, Heterocyclic Compounds, Drug Discovery, medicine, Moiety, Humans, Molecular Biology, biology, Bicyclic molecule, Organic Chemistry, Antagonist, In vitro, chemistry, CCR5 Receptor Antagonists, biology.protein, HIV-1, Molecular Medicine, HeLa Cells
Abstract

Replacement of the large hydantoin-indole moiety from our previous work with a variety of smaller heterocyclic analogues gave rise to potent CCR5 antagonists having binding affinity comparable to the hydantoin analogues. The synthesis, SAR, and biological profiles of this class of antagonists are described.

Published
2001

32. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 3: a proposed pharmacophore model for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-[4-(substituted)piperidin-1-yl]butanes

Author

Shrenik K. Shah, Julie A. DeMartino, Lorraine Malkowitz, Bryan Oates, Jennifer L. Loebach, Sandra L. Gould, Laura C. Meurer, Martin S. Springer, Malcolm MacCoss, Paul E. Finke, Laurie A. Castonguay, and Sander G. Mills

Subjects
Models, Molecular, Chemokine receptor CCR5, Stereochemistry, Anti-HIV Agents, Neutrophils, Clinical Biochemistry, Pharmaceutical Science, CCR5 receptor antagonist, Biochemistry, Chemical synthesis, Models, Biological, chemistry.chemical_compound, Inhibitory Concentration 50, Structure-Activity Relationship, Piperidines, Cricetinae, Drug Discovery, Structure–activity relationship, Animals, Humans, Chemokine CCL4, Molecular Biology, Cells, Cultured, chemistry.chemical_classification, biology, Organic Chemistry, Antagonist, Macrophage Inflammatory Proteins, Sulfonamide, chemistry, CCR5 Receptor Antagonists, biology.protein, Butanes, Molecular Medicine, Pharmacophore, Derivative (chemistry)
Abstract

Structure-activity relationship studies directed toward the optimization of (2S)-2-(3-chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[4-(substituted)piperidin-1-yl]butanes as CCR5 antagonists resulted in the synthesis of the spiro-indanone derivative 8c (IC50=5 nM). These and previous results are summarized in a proposed pharmacophore model for this class of CCR5 antagonist.

Published
2001

33. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 1: discovery of the pyrrolidine scaffold and determination of its stereochemical requirements

Author

Sandra L. Gould, Martin S. Springer, Julie A. DeMartino, Salvatore J. Siciliano, Richard J. Budhu, Malcolm MacCoss, Sander G. Mills, Lorraine Malkowitz, and Jeffrey J. Hale

Subjects
Pyrrolidines, Receptors, CCR5, Stereochemistry, Chemokine receptor CCR5, Clinical Biochemistry, Molecular Conformation, Pharmaceutical Science, CCR5 receptor antagonist, CHO Cells, Transfection, Biochemistry, Chemical synthesis, Binding, Competitive, Pyrrolidine, Sulfone, Iodine Radioisotopes, chemistry.chemical_compound, Cricetinae, Drug Discovery, Animals, Chemokine CCL4, Molecular Biology, biology, Chemistry, Chinese hamster ovary cell, Organic Chemistry, Regioselectivity, Macrophage Inflammatory Proteins, CCR5 Receptor Antagonists, biology.protein, Molecular Medicine, Stereoselectivity
Abstract

A series of 1,3,4-trisubstituted pyrrolidines was discovered to have the ability to displace [ 125 I]-MIP-1α from the CCR5 receptor expressed on Chinese hamster ovary (CHO) cell membranes. CCR5 activity was found to be dependent on the regiochemistry and the absolute stereochemistry of the pyrrolidine.

Published
2001

34. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. part 1: discovery and initial structure-activity relationships for 1 -amino-2-phenyl-4-(piperidin-1-yl)butanes

Author

Janet Lineberger, Salvatore J. Siciliano, Michael W. Miller, Karen Holmes, Lorraine Malkowitz, Renee Danzeisen, Richard J. Budhu, Joseph Kessler, Conrad P. Dorn, Julie A. DeMartino, Malcolm MacCoss, Gwen Carver, Bruce L. Daugherty, William A. Schleif, Bryan Oates, Martin S. Springer, Emilio A. Emini, Paul E. Finke, Daria J. Hazuda, Sander G. Mills, Anthony Carella, and Sandra L. Gould

Subjects
Receptors, CCR5, Chemokine receptor CCR5, Stereochemistry, Anti-HIV Agents, Clinical Biochemistry, Pharmaceutical Science, CCR5 receptor antagonist, CHO Cells, Transfection, Biochemistry, Chemical synthesis, chemistry.chemical_compound, Inhibitory Concentration 50, Structure-Activity Relationship, Piperidines, Cricetinae, Drug Discovery, Structure–activity relationship, Animals, Combinatorial Chemistry Techniques, Humans, Chemokine CCL4, Molecular Biology, chemistry.chemical_classification, biology, Organic Chemistry, Benzothiophene, Sulfoxide, Macrophage Inflammatory Proteins, Sulfonamide, chemistry, CCR5 Receptor Antagonists, biology.protein, Molecular Medicine, Sample collection, Protein Binding
Abstract

Screening of the Merck sample collection for compounds with CCR5 receptor binding afforded (2 S )-2-(3,4-dichlorophenyl)-1-[ N -(methyl)- N -(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4′-piperidin-1′-yl)]butane S -oxide ( 4 ) as a potent lead structure having an IC 50 binding affinity of 35 nM. Herein, we describe the discovery of this lead structure and our initial structure–activity relationship studies directed toward the requirement for and optimization of the 1-amino fragment.

Published
2001

35. Two-site binding of C5a by its receptor: an alternative binding paradigm for G protein-coupled receptors

Author

G Van Riper, Zenon Konteatis, Stephen C. Bondy, S J Siciliano, Martin S. Springer, Lorraine Malkowitz, Julie A. DeMartino, Hugh Rosen, and Thomas E. Rollins

Subjects
Neutrophils, Protein Conformation, Molecular Sequence Data, Complement C5a, Biology, Transfection, Models, Biological, C5a receptor, Structure-Activity Relationship, GTP-Binding Proteins, Humans, 5-HT5A receptor, Binding site, Cloning, Molecular, Receptor, Receptor, Anaphylatoxin C5a, Protease-activated receptor 2, G protein-coupled receptor, Multidisciplinary, Binding Sites, Membranes, Base Sequence, Dose-Response Relationship, Drug, Peptide Fragments, Receptors, Complement, Biochemistry, Mutagenesis, Signal transduction, Sequence Analysis, Binding domain, Signal Transduction, Research Article
Abstract

The guanine nucleotide-binding protein-coupled receptor superfamily binds a vast array of biological messengers including lipids, odorants, catecholamines, peptides, and proteins. While some small molecules bind to these receptors at a single interhelical site, we find that the binding domain on the receptor for the inflammatory protein C5a is more complex and consists of two distinct subsites. This more elaborate motif appears to be an evolutionary adaptation of the simpler paradigm to which a second interaction site has been added in the receptor N terminus. Surprisingly, occupation of only one of the subsites is required for receptor activation. The two-site motif is not unique to the C5a receptor but appears to be widely used by the superfamily to accommodate macromolecular ligands.

Published
1994

36. Screening for potassium channel modulators by a high through-put 86-rubidium efflux assay in a 96-well microtiter plate

Author

Lorraine Malkowitz, Wang Hsuei-Chin, Bernard Beer, Arthur J. Blume, M.Reza Ziai, and Selwyn Daniel

Subjects
Pharmacology, Potassium Channels, Dose-Response Relationship, Drug, Chemistry, Potassium, Calcitonin Gene-Related Peptide, Diazoxide, chemistry.chemical_element, Substrate (chemistry), Membrane transport, Potassium channel, Rubidium, Microtiter plate, Adenosine Triphosphate, Biochemistry, Adherent cell, Humans, Efflux, Rubidium Radioisotopes, Cells, Cultured
Abstract

A rapid and sensitive 86Rb efflux assay to detect chemical compounds capable of modulating the ATP-dependent potassium (KATP) channel is described. This assay, which is performed in a 96-well microtiter plate, utilizes a substrate adherent cell line as the target, requires a small amount of 86Rb as the tracer, and is a suitable system for performing the biochemical and pharmacological characterization of the KATP-channel and its activators. Because this assay is amenable to automation, it presents a useful means for high-volume screening of chemical compounds on a routine basis.

Published
1991

37. Label-Free High-Throughput Screening via Mass Spectrometry: A Single Cystathionine Quantitative Method for Multiple Applications.

Author

Tom G. Holt, Bernard K. Choi, Neil S. Geoghagen, Kristian K. Jensen, Qi Luo, William A. LaMarr, Gergely M. Makara, Lorraine Malkowitz, Can C. Ozbal, Yusheng Xiong, Claude Dufresne, and Ming-Juan Luo

Subjects
HIGH throughput screening (Drug development), MASS spectrometry, QUANTITATIVE research, ENZYME-linked immunosorbent assay, DRUG analysis, CARDIOVASCULAR agents, DRUG development
Abstract

Label-free mass spectrometric (MS) technologies are particularly useful for enzyme assay design for drug discovery screens. MS permits the selective detection of enzyme substrates or products in a wide range of biological matrices without need for derivatization, labeling, or capture technologies. As part of a cardiovascular drug discovery effort aimed at finding modulators of cystathionine beta-synthase (CBS), we used the RapidFire®label-free high-throughput MS (HTMS) technology to develop a high-throughput screening (HTS) assay for CBS activity. Thein vitro assay used HTMS to quantify the unlabeled product of the CBS reaction, cystathionine. Cystathionine HTMS analyses were carried out with a throughput of 7 s per sample and quantitation over a linear range of 80–10,000 nM. A compound library of 25,559 samples (or 80 384-well plates) was screened as singlets using the HTMS assay in a period of 8 days. With a hit rate of 0.32, the actives showed a 90 confirmation rate. Thein vitro assay was applied to secondary screens in more complex matrices with no additional analytical development. Our results show that the HTMS method was useful for screening samples containing serum, for cell-based assays, and for liver explants. The novel extension of thein vitro analytical method, without modification, to secondary assays resulted in a significant and advantageous economy of development time for the drug discovery project. [ABSTRACT FROM AUTHOR]

Published
2009
Full Text
View/download PDF

38. Calcium Binding Protein in Squid Brain: Biochemical Similarity to the 28,000-MrVitamin D-Dependent Calcium Binding Protein (Calbindin-D28k)

Author

Sylvia Christakos, Lorraine Malkowitz, Susan C. Feldman, Alan J. Sori, and Andrea Sperduto

Subjects
Protein Denaturation, Hot Temperature, Population, chemistry.chemical_element, Biology, Calcium, Nervous System, Biochemistry, Calbindin, Immunoenzyme Techniques, Cellular and Molecular Neuroscience, S100 Calcium Binding Protein G, Calcium-binding protein, Animals, Isoelectric Point, Amino Acids, Tyrosine, education, Brain Chemistry, Chromatography, education.field_of_study, Histocytochemistry, musculoskeletal, neural, and ocular physiology, Binding protein, Calcium-Binding Proteins, Decapodiformes, Vitamin D-dependent calcium-binding protein, Molecular Weight, Isoelectric point, nervous system, chemistry, Electrophoresis, Polyacrylamide Gel
Abstract

A calcium binding protein that is biochemically similar to vertebrate 28,000-Mr vitamin D-dependent calcium binding protein (calbindin-D28k) has been purified from squid brain. Squid brain calbindin was found to have an isoelectric point of 5.0, was heat stable up to 60 degrees C, and showed increased electrophoretic mobility in the presence of chelator. Amino acid analysis revealed a high content of glutamic and aspartic acids and a low level of methionine, histidine, and tyrosine, a finding similar but not identical to the composition of vertebrate calbindin-D28k. The molecular weight of the squid protein, determined by Ferguson plot analysis of data obtained from sodium dodecyl sulfate-gel electrophoresis, was calculated to be 25,700, as compared with 27,800 for rat renal calbindin. Immunocytochemical analysis demonstrated immunoreactive protein in a selected population of neurons and fibers in several areas of the molluscan nervous system. This study represents the first purification from an invertebrate of a calcium binding protein that is biochemically similar to vitamin D-dependent calcium binding protein. These results demonstrate that calbindin, although not identical in vertebrates and cephalopods, may be phylogenetically conserved in structure. The restricted distribution of immunoreactive calbindin in both the cephalopod and mammalian brain suggests that the function of neuronal calbindin may also be conserved in evolution.

Published
1987
Full Text
View/download PDF

39. Administration of 1,25-dihydroxyvitamin D3 results in the elevation of hippocampal seizure threshold levels in rats

Author

Sylvia Christakos, Martin J. Moskovits, Allan Siegel, and Lorraine Malkowitz

Subjects
Vitamin, Male, medicine.medical_specialty, Stimulation, Hippocampal formation, Hippocampus, chemistry.chemical_compound, Calcitriol, Seizures, Internal medicine, Convulsion, medicine, Vitamin D and neurology, Hippocampus (mythology), Animals, Receptor, Molecular Biology, Seizure threshold, business.industry, General Neuroscience, Electroencephalography, Rats, Inbred Strains, Electric Stimulation, Rats, Endocrinology, chemistry, Neurology (clinical), medicine.symptom, business, Developmental Biology
Abstract

Electrical stimulation of the dorsal hippocampal formation of the rat was employed to determine the effect of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), the hormonal form of vitamin D, on induced seizure thresholds. Stereotaxic injection of 100 micrograms or 50 micrograms 1,25-dihydroxyvitamin D3 in 2 microliter propylene glycol into the hippocampus resulted in a significant elevation in seizure threshold in all animals treated. 1,25-dihydroxyvitamin D3-induced increases were noted within 5-10 min and lasted at least 120-180 min after injection when the experiments were terminated. Intravenous injection of 1,25-(OH)2D3 also resulted in a significant elevation of seizure threshold; however, the increase was transient, lasting only 30 min. This effect was specific since 200 micrograms vitamin D3 or 200 micrograms 25-hydroxyvitamin D3 (25-(OH)D3), injected into the hippocampus, had no effect on seizure threshold levels. This investigation represents the first direct demonstration of a role for 1,25-(OH)2D3 in the regulation of seizure activity and suggests, along with the previously demonstrated presence of immunoreactive vitamin D-dependent calcium binding protein and receptors for 1,25-dihydroxyvitamin D3 in the brain, that the vitamin D endocrine system may play a significant role in the physiological mechanisms underlying convulsive disorders.

Published
1984

40. Diabetes and renal calcium binding protein in the rat

Author

Harold P. Schedl, Lorraine Malkowitz, Sylvia Christakos, R. L. Horst, and Helen D. Wilson

Subjects
Blood Glucose, Male, medicine.medical_specialty, Calcitriol, medicine.medical_treatment, chemistry.chemical_element, Calcium, Kidney, General Biochemistry, Genetics and Molecular Biology, Diabetes Mellitus, Experimental, Excretion, chemistry.chemical_compound, Internal medicine, Calcium-binding protein, medicine, Animals, Insulin, Calcifediol, Body Weight, Calcium-Binding Proteins, Rats, Inbred Strains, Urinary calcium, Rats, medicine.anatomical_structure, Endocrinology, chemistry, medicine.drug
Abstract

Renal calcium binding protein (CaBP), a vitamin D-dependent protein of 28,000 Mr, may be involved in calcium transport by cells of the renal tubule. The streptozotocin-diabetic rat is hypercalciuric and shows markedly decreased concentration of 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] in serum and of CaBP in small intestine. To examine the relationship of renal CaBP in diabetes to 1,25-(OH)2D3 and urinary calcium excretion, renal CaBP, serum 1,25-(OH)2D3, and urinary calcium were measured in control, diabetic, and insulin-treated diabetic rats. Treatment of the diabetic rat with insulin decreased urinary calcium excretion and elevated 1,25-(OH)2D3 toward normal. Renal CaBP was found to be the same in controls and diabetics despite a tenfold difference in concentration of 1,25-(OH)2D3 in serum, and to be unaffected by insulin treatment, which elevated 1,25-(OH)2D3 by a factor of 7 above untreated diabetics. It is concluded that in the diabetic rat either (1) the threshold concentration of 1,25-(OH)2D3 for inducing synthesis of renal CaBP is set at a much lower level than that for intestinal CaBP, or (2) since both 1,25-(OH)2D3 and renal CaBP are produced in the kidney, 1,25-(OH)2D3 exerts a paracrine effect on renal CaBP production because of its high local concentration. The increased urinary calcium excretion in the untreated streptozotocin-diabetic rat is not secondary to an alteration in renal CaBP.

Published
1984

Catalog

Books, media, physical & digital resources
See catalog results