Search

Your search keyword '"Mu‑Yun Gao"' showing total 3 results
Start Over Author "Mu‑Yun Gao" Journal journal of medicinal chemistry
3 results on '"Mu‑Yun Gao"'

1. Structure-Based Design of Selective LONP1 Inhibitors for Probing In Vitro Biology

Author

Mari Manuia, Wenshuo Lu, Laura J. Kingsley, Zhiwei Ma, Vicki Zhou, Darbi Witmer, Glen Spraggon, Mu-Yun Gao, Pierre-Yves Michellys, Min Lu, Yong Jia, Matthew McNeill, Sarah Greenblatt, Bender Steven Lee, Andreas Kreusch, Gerald Lelais, Xiaohui He, Victor Nikulin, Mei-Ting Vaillancourt, Christian C. Lee, Jacob R. Haling, John Nelson, and Ajay A. Vashisht

Subjects
Drug, 0303 health sciences, Protease, Cancer cell proliferation, media_common.quotation_subject, medicine.medical_treatment, 01 natural sciences, 20s proteasome, In vitro, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, 03 medical and health sciences, chemistry.chemical_compound, chemistry, Biochemistry, Drug Discovery, medicine, Molecular Medicine, Structure based, Protein folding, Boronic acid, 030304 developmental biology, media_common
Abstract

LONP1 is an AAA+ protease that maintains mitochondrial homeostasis by removing damaged or misfolded proteins. Elevated activity and expression of LONP1 promotes cancer cell proliferation and resistance to apoptosis-inducing reagents. Despite the importance of LONP1 in human biology and disease, very few LONP1 inhibitors have been described in the literature. Herein, we report the development of selective boronic acid-based LONP1 inhibitors using structure-based drug design as well as the first structures of human LONP1 bound to various inhibitors. Our efforts led to several nanomolar LONP1 inhibitors with little to no activity against the 20S proteasome that serve as tool compounds to investigate LONP1 biology.

Published
2021
Full Text
View/download PDF

2. Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases

Author

Glen Spraggon, Smith Jeffrey M, Chianelli Donatella, Advait Nagle, Christian Wiesmann, Xiaodong Liu, Yongping Xie, Richard J. Sciotti, Todd Groessl, Kevin Johnson, Xianzhong Liu, Celine Be, Christopher Thompson, Yin H. Lai, Jan Jiricek, Patrick J Rudewicz, Brandon S. Pybus, Casey J. N. Mathison, Valentina Molteni, Honnappa Srinivas, Richard Glynne, Jaime Ballard, Agnes Biggart, Diana Caridha, Andreas Hein, Ashley Mitchell Berman, Mu-Yun Gao, Lauren C. Davis, Michael Shapiro, Michael Gibney, Yen Liang Chen, Vince Yeh, Fabian K. Eggimann, Badry Bursulaya, Mara Kreishman-Deitrick, Lerario Isabelle K, Fang Liang, Shilpi Khare, Wendy Richmond, Srinivasa P. S. Rao, Frantisek Supek, Tove Tuntland, and Alexandre Luneau

Subjects
Chagas disease, Antiprotozoal Agents, Drug Annotation, 01 natural sciences, Rats, Sprague-Dawley, Mice, 03 medical and health sciences, Dogs, parasitic diseases, Drug Discovery, medicine, Animals, Humans, African trypanosomiasis, Oxazoles, Leishmania major, 030304 developmental biology, Mice, Inbred BALB C, 0303 health sciences, Chemistry, Leishmania tarentolae, Leishmaniasis, Triazoles, medicine.disease, Virology, Rats, 0104 chemical sciences, 3. Good health, Macaca fascicularis, 010404 medicinal & biomolecular chemistry, Pyrimidines, Visceral leishmaniasis, Liver, Proteasome, Proteasome inhibitor, Leishmaniasis, Visceral, Molecular Medicine, Proteasome Inhibitors, Leishmania donovani, Clearance, medicine.drug
Abstract

Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. Furthermore, we present high-resolution cryo-EM structures of the Leishmania tarentolae proteasome in complex with LXE408, which provides a compelling explanation for the noncompetitive mode of binding of this novel class of inhibitors of the kinetoplastid proteasome.

Published
2020
Full Text
View/download PDF

3. Structure-Based Design of Selective LONP1 Inhibitors for Probing

Author

Laura J, Kingsley, Xiaohui, He, Matthew, McNeill, John, Nelson, Victor, Nikulin, Zhiwei, Ma, Wenshuo, Lu, Vicki W, Zhou, Mari, Manuia, Andreas, Kreusch, Mu-Yun, Gao, Darbi, Witmer, Mei-Ting, Vaillancourt, Min, Lu, Sarah, Greenblatt, Christian, Lee, Ajay, Vashisht, Steven, Bender, Glen, Spraggon, Pierre-Yves, Michellys, Yong, Jia, Jacob R, Haling, and Gérald, Lelais

Subjects
Proteasome Endopeptidase Complex, Binding Sites, Cell Survival, Boronic Acids, Cell Line, Bortezomib, Mitochondrial Proteins, Molecular Docking Simulation, Protein Subunits, Structure-Activity Relationship, ATP-Dependent Proteases, Drug Design, Humans, Protease Inhibitors
Abstract

LONP1 is an AAA+ protease that maintains mitochondrial homeostasis by removing damaged or misfolded proteins. Elevated activity and expression of LONP1 promotes cancer cell proliferation and resistance to apoptosis-inducing reagents. Despite the importance of LONP1 in human biology and disease, very few LONP1 inhibitors have been described in the literature. Herein, we report the development of selective boronic acid-based LONP1 inhibitors using structure-based drug design as well as the first structures of human LONP1 bound to various inhibitors. Our efforts led to several nanomolar LONP1 inhibitors with little to no activity against the 20S proteasome that serve as tool compounds to investigate LONP1 biology.

Published
2021

Catalog

Books, media, physical & digital resources
See catalog results