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1,075 results on '"Perlin, David S."'

201. Novel FKS1 and FKS2 modifications in a high-level echinocandin resistant clinical isolate of Candida glabrata

Author

Hou, Xin, primary, Healey, Kelley R., additional, Shor, Erika, additional, Kordalewska, Milena, additional, Ortigosa, Cristina Jiménez, additional, Paderu, Padmaja, additional, Xiao, Meng, additional, Wang, He, additional, Zhao, Ying, additional, Lin, Li-Yan, additional, Zhang, Yan-Hai, additional, Li, Yong-Zhe, additional, Xu, Ying-Chun, additional, Perlin, David S., additional, and Zhao, Yanan, additional

Published
2019
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202. Emergence of Echinocandin Resistance due to a Point Mutation in the fks1 Gene in a Patient with Chronic Pulmonary Aspergillosis

Author

Jiménez-Ortigosa, Cristina, Moore, Caroline, Denning, David, and Perlin, David S.

Subjects
skin and connective tissue diseases, bacterial infections and mycoses
Abstract

We have identified the first case of fks1 hot spot 1 point mutation causing echinocandin resistance in a clinical Aspergillus fumigatus isolate recovered from a patient with an aspergilloma and chronic pulmonary aspergillosis who first failed azole therapy and then was treated with micafungin.

Published
2017

206. Epidemiology of candidemia in Shiraz, southern Iran: A prospective multicenter study (2016–2018).

Author

Arastehfar, Amir, Yazdanpanah, Samira, Bakhtiari, Mina, Fang, Wenjie, Pan, Weihua, Mahmoudi, Shahram, Pakshir, Keyvan, Daneshnia, Farnaz, Boekhout, Teun, Ilkit, Macit, Perlin, David S, Zomorodian, Kamiar, and Zand, Farid

Abstract

Systematic candidemia studies, especially in southern Iran, are scarce. In the current prospective study, we investigated candidemia in three major healthcare centers of Shiraz, the largest city in southern Iran. Yeast isolates from blood and other sterile body fluids were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and subjected to antifungal susceptibility testing (AFST) using the broth microdilution method. Clinical data were retrieved from patients' medical records. In total, 113 yeast isolates were recovered from 109 patients, over 60% of whom received fluconazole. Antifungal drugs were prescribed without considering species identification or AFST. The all-cause mortality rate was 28%. Almost 30% of the patients were from intensive care units (ICUs). Candida albicans (56/113; 49.5%) was the most prevalent species followed by C. glabrata (26/113; 23%), C. parapsilosis (13/113; 11.5%), C. tropicalis (7/113; 6.2%), and C. dubliniensis (5/113; 4.4%). Only five isolates showed antifungal resistance or decreased susceptibility to fluconazole: one C. orthopsilosis isolate from an azole-naïve patient and two C. glabrata , one C. albicans , and one C. dubliniensis isolates from patients treated with azoles, who developed therapeutic failure against azoles later. Our results revealed a low level of antifungal resistance but a notable rate of azole therapeutic failure among patients with candidemia due to non- albicans Candida species, which threaten the efficacy of fluconazole, the most widely used antifungal in southern regions of Iran. Candidemia studies should not be confined to ICUs and treatment should be administered based on species identification and AFST results. [ABSTRACT FROM AUTHOR]

Published
2021
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208. Genetically related micafungin-resistant Candida parapsilosis blood isolates harbouring novel mutation R658G in hotspot 1 of Fks1p: a new challenge?

Author

Arastehfar, Amir, Daneshnia, Farnaz, Hilmioglu-Polat, Süleyha, Ilkit, Macit, Yasar, Melike, Polat, Furkan, Metin, Dilek Yeşim, Dokumcu, Ülküm Zafer, Pan, Weihua, Hagen, Ferry, Boekhout, Teun, Perlin, David S, and Lass-Flörl, Cornelia

Subjects
CANDIDEMIA, AMPHOTERICIN B, PEDIATRIC gastroenterology, CANDIDA, BLOOD, CHILD patients
Abstract

Background: Echinocandin resistance rarely occurs in clinical Candida parapsilosis isolates and the underlying mechanism is unknown.Objectives: To determine the prevalence of echinocandin resistance and the underlying mechanism for a large collection of C. parapsilosis blood isolates and to determine whether the echinocandin-resistant isolates were clonally related.Methods: C. parapsilosis blood isolates (n = 213) were subjected to antifungal susceptibility testing (CLSI M27), for micafungin, anidulafungin, amphotericin B and, if appropriate, caspofungin. Hotspot (HS) 1 and HS2 of FKS1 were sequenced for all isolates (n = 213) and microsatellite typing was performed for echinocandin-resistant isolates.Results: All isolates were susceptible to amphotericin B and two isolates were intermediate to anidulafungin (MIC = 4 mg/L), while micafungin resistance was noted in four isolates (MIC >8 mg/L); three of which were also fluconazole resistant and therefore were MDR. Interestingly, micafungin-resistant isolates, but not those intermediate to anidulafungin, carried novel mutation R658G in HS1 of Fks1p; three of which also harboured Y132F+K143R in Erg11. The first isolate (MICR1) was recovered in November 2017 from a patient admitted to paediatric gastroenterology who showed therapeutic failure under caspofungin treatment. MICR2-MICR4 were collected during 2018-19 and were recovered from three echinocandin-naive paediatric-surgery patients; the isolates shared the same genotype.Conclusions: Herein, for the first time (to the best of our knowledge), we identified micafungin-resistant C. parapsilosis blood isolates harbouring a novel mutation in HS1 of FKS1, which was likely attributable to in vitro micafungin resistance and in vivo caspofungin therapeutic failure. The acquisition of micafungin-resistant C. parapsilosis isolates in echinocandin-naive patients likely implicates clonal expansion, as supported by the close genetic relatedness of MICR2-MICR4. [ABSTRACT FROM AUTHOR]

Published
2021
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209. Review of the Novel Echinocandin Antifungal Rezafungin: Animal Studies and Clinical Data.

Author

Yanan Zhao and Perlin, David S.

Subjects
*ECHINOCANDINS, *ANTIFUNGAL agents, *CLINICAL trials, *MYCOSES, *PHARMACOKINETICS
Abstract

Rezafungin is a novel echinocandin drug being developed as a first-line option for treatment and prevention of invasive fungal infections. As a result of a structural modification in its parent molecule anidulafungin, rezafungin has acquired unique chemical stability conferring prolonged pharmacokinetics, as well as an administration advantage in the clinical setting compared to other drugs in the same class. Rezafungin displays potent in vitro activity against a wide spectrum of fungal pathogens, which is reflected in robust in vivo efficacy and/or pharmacodynamic studies using various animal models as well as in promising clinical trials data. This review describes in vivo characterization of rezafungin using animal models, current status of clinical development and key findings from these studies. [ABSTRACT FROM AUTHOR]

Published
2020
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210. Isavuconazole Prophylaxis in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients.

Author

Fontana, Lauren, Perlin, David S, Zhao, Yanan, Noble, Brie N, Lewis, James S, Strasfeld, Lynne, and Hakki, Morgan

Subjects
*BLOOD disease treatment, *ANTIFUNGAL agents, *HEMATOPOIETIC stem cell transplantation, *MEDICAL records, *PREVENTIVE medicine, *MYCOSES, *NEUTROPENIA, *PULMONARY aspergillosis, *TRANSPLANTATION of organs, tissues, etc., *ACUTE myeloid leukemia, *TREATMENT effectiveness, *RETROSPECTIVE studies, *ACQUISITION of data methodology, *DISEASE complications, *EVALUATION
Abstract

Background Isavuconazole (ISA) is an attractive candidate for primary mold-active prophylaxis in high-risk patients with hematologic malignancies or hematopoietic cell transplant (HCT) recipients. However, data supporting the use of ISA for primary prophylaxis in these patients are lacking. Methods We conducted a retrospective review of breakthrough invasive fungal infections (bIFIs) among adult hematologic malignancy patients and HCT recipients who received ≥7 days of ISA primary prophylaxis between 1 September 2016 and 30 September 2018. The incidence of bIFIs in patients receiving ISA was compared to those receiving posaconazole (POS) and voriconazole (VOR) during the same time period. Results One hundred forty-five patients received 197 courses of ISA prophylaxis. Twelve bIFIs (Aspergillus fumigatus [5], Aspergillus species [2], Mucorales [2], Fusarium species [2], and Candida glabrata [1]) occurred, representing 8.3% of patients and 6.1% of courses, after a median duration of 14 days of ISA prophylaxis. All bIFIs occurred during periods of neutropenia. Seven patients (58.3%) died within 42 days of onset of bIFI. In addition, bIFIs complicated 10.2% of ISA, 4.1% of POS, and 1.1% of VOR courses among patients with de novo or relapsed/refractory acute myeloid leukemia during the study period, with invasive pulmonary aspergillosis (IPA) complicating 6.8% of ISA, 1.3% of POS, and zero VOR courses. Conclusions Although ISA has been approved for treatment of invasive Aspergillus and mucormycosis, we observed an increased rate of bIFI, notably IPA, using ISA for primary prophylaxis. These results support the need for further study to determine the role of ISA as primary prophylaxis. [ABSTRACT FROM AUTHOR]

Published
2020
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211. 2385. Ceftazidime–Avibactam in Combination With Fosfomycin: A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa

Author

Papp-Wallace, Krisztina M, primary, Zeiser, Elise T, additional, Becka, Scott A, additional, Park, Steven T, additional, Winkler, Marisa L, additional, Nguyen, Kevin, additional, Singh, Indresh, additional, Sutton, Granger, additional, Fouts, Derrick E, additional, Ellis-Grosse, Evelyn J, additional, Drusano, George L, additional, Perlin, David S, additional, and Bonomo, Robert A, additional

Published
2018
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215. Molecular Analysis of Resistance and Detection of Non-Wild-Type Strains Using Etest Epidemiological Cutoff Values for Amphotericin B and Echinocandins for Bloodstream Candida Infections from a Tertiary Hospital in Qatar

Author

Taj-Aldeen, Saad J., primary, Salah, Husam, additional, Perez, Winder B., additional, Almaslamani, Muna, additional, Motyl, Mary, additional, AbdulWahab, Atqah, additional, Healey, Kelley R., additional, and Perlin, David S., additional

Published
2018
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216. Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo

Author

Vickers, Clare F., primary, Silva, Ana P. G., additional, Chakraborty, Ajanta, additional, Fernandez, Paulina, additional, Kurepina, Natalia, additional, Saville, Charis, additional, Naranjo, Yandi, additional, Pons, Miquel, additional, Schnettger, Laura S., additional, Gutierrez, Maximiliano G., additional, Park, Steven, additional, Kreiswith, Barry N., additional, Perlin, David S., additional, Thomas, Eric J., additional, Cavet, Jennifer S., additional, and Tabernero, Lydia, additional

Published
2018
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218. Multilocus Sequence Typing (MLST) Genotypes of Candida glabrata Bloodstream Isolates in Korea: Association With Antifungal Resistance, Mutations in Mismatch Repair Gene (Msh2), and Clinical Outcomes

Author

Byun, Seung A., primary, Won, Eun Jeong, additional, Kim, Mi-Na, additional, Lee, Wee Gyo, additional, Lee, Kyungwon, additional, Lee, Hye Soo, additional, Uh, Young, additional, Healey, Kelley R., additional, Perlin, David S., additional, Choi, Min Ji, additional, Kim, Soo Hyun, additional, and Shin, Jong Hee, additional

Published
2018
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219. Comparative study of Candida spp. isolates: Identification and echinocandin susceptibility in isolates obtained from blood cultures in 15 hospitals in Medellín, Colombia

Author

Berrio, Indira, primary, Maldonado, Natalia, additional, De Bedout, Catalina, additional, Arango, Karen, additional, Cano, Luz Elena, additional, Valencia, Yorlady, additional, Jiménez-Ortigosa, Cristina, additional, Perlin, David S., additional, Gómez, Beatriz L., additional, Robledo, Carlos, additional, and Robledo, Jaime, additional

Published
2018
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220. Absence of Azole or Echinocandin Resistance in Candida glabrata Isolates in India despite Background Prevalence of Strains with Defects in the DNA Mismatch Repair Pathway

Author

Singh, Ashutosh, primary, Healey, Kelley R., additional, Yadav, Priyanka, additional, Upadhyaya, Gargi, additional, Sachdeva, Neelam, additional, Sarma, Smita, additional, Kumar, Anil, additional, Tarai, Bansidhar, additional, Perlin, David S., additional, and Chowdhary, Anuradha, additional

Published
2018
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222. VT-1598 inhibits the in vitro growth of mucosal Candida strains and protects against fluconazole-susceptible and -resistant oral candidiasis in IL-17 signalling-deficient mice

Author

Break, Timothy J, primary, Desai, Jigar V, additional, Healey, Kelley R, additional, Natarajan, Mukil, additional, Ferre, Elise M N, additional, Henderson, Christina, additional, Zelazny, Adrian, additional, Siebenlist, Ulrich, additional, Yates, Christopher M, additional, Cohen, Oren J, additional, Schotzinger, Robert J, additional, Perlin, David S, additional, Garvey, Edward P, additional, and Lionakis, Michail S, additional

Published
2018
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224. Correction for Yang et al., “Tolerance to Caspofungin in Candida albicans Is Associated with at Least Three Distinctive Mechanisms That Govern Expression of FKS Genes and Cell Wall Remodeling”

Author

Yang, Feng, primary, Zhang, Lulu, additional, Wakabayashi, Hironao, additional, Myers, Jason, additional, Jiang, Yuanying, additional, Cao, Yongbing, additional, Jimenez-Ortigosa, Cristina, additional, Perlin, David S., additional, and Rustchenko, Elena, additional

Published
2018
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227. A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009–17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance

Author

Chowdhary, Anuradha, primary, Prakash, Anupam, additional, Sharma, Cheshta, additional, Kordalewska, Milena, additional, Kumar, Anil, additional, Sarma, Smita, additional, Tarai, Bansidhar, additional, Singh, Ashutosh, additional, Upadhyaya, Gargi, additional, Upadhyay, Shalini, additional, Yadav, Priyanka, additional, Singh, Pradeep K, additional, Khillan, Vikas, additional, Sachdeva, Neelam, additional, Perlin, David S, additional, and Meis, Jacques F, additional

Published
2018
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233. Potential Use of MALDI-ToF Mass Spectrometry for Rapid Detection of Antifungal Resistance in the Human Pathogen Candida glabrata

Author

Vella, Antonietta, De Carolis, Elena, Mello Dottoressa, Enrica, Perlin, David S., Sanglard, Dominique, Sanguinetti, Maurizio, Posteraro, Brunella, De Carolis, Elena (ORCID:0000-0003-4757-7256), Mello, Enrica, Sanguinetti, Maurizio (ORCID:0000-0002-9780-7059), Posteraro, Brunella (ORCID:0000-0002-1663-7546), Vella, Antonietta, De Carolis, Elena, Mello Dottoressa, Enrica, Perlin, David S., Sanglard, Dominique, Sanguinetti, Maurizio, Posteraro, Brunella, De Carolis, Elena (ORCID:0000-0003-4757-7256), Mello, Enrica, Sanguinetti, Maurizio (ORCID:0000-0002-9780-7059), and Posteraro, Brunella (ORCID:0000-0002-1663-7546)

Abstract

The echinocandins are relatively new antifungal drugs that represent, together with the older azoles, the recommended and/or preferred agents to treat candidaemia and other forms of invasive candidiasis in human patients. If "time is of the essence" to reduce the mortality for these infections, the administration of appropriate antifungal therapy could be accelerated by the timely reporting of laboratory test results. In this study, we attempted to validate a MALDI-ToF mass spectrometry-based assay for the antifungal susceptibility testing (AFST) of the potentially multidrug-resistant pathogen Candida glabrata against anidulafungin and fluconazole. The practical applicability of the assay, reported here as MS-AFST, was assessed with a panel of clinical isolates that were selected to represent phenotypically and genotypically/molecularly susceptible or resistant strains. The data show the potential of our assay for rapid detection of antifungal resistance, although the MS-AFST assay performed at 3 h of the in vitro antifungal exposure failed to detect C. glabrata isolates with echinocandin resistance-associated FKS2 mutations. However, cell growth kinetics in the presence of anidulafungin revealed important cues about the in vitro fitness of C. glabrata isolates, which may lead to genotypic or phenotypic antifungal testing in clinical practice.

Published
2017

241. Expression Dynamics of Innate Immunity in Influenza Virus-Infected Swine

Author

Montoya, María, primary, Foni, Emanuela, additional, Solórzano, Alicia, additional, Razzuoli, Elisabetta, additional, Baratelli, Massimiliano, additional, Bilato, Dania, additional, Córdoba, Lorena, additional, del Burgo, Maria Angeles Martín, additional, Martinez, Jorge, additional, Martinez-Orellana, Pamela, additional, Chiapponi, Chiara, additional, Perlin, David S., additional, del Real, Gustavo, additional, and Amadori, Massimo, additional

Published
2017
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242. Changes in In Vitro Susceptibility Patterns of Aspergillus to Triazoles and Correlation With Aspergillosis Outcome in a Tertiary Care Cancer Center, 1999–2015

Author

Heo, Sang Taek, primary, Tatara, Alexander M., additional, Jiménez-Ortigosa, Cristina, additional, Jiang, Ying, additional, Lewis, Russell E., additional, Tarrand, Jeffrey, additional, Tverdek, Frank, additional, Albert, Nathaniel D., additional, Verweij, Paul E., additional, Meis, Jacques F., additional, Mikos, Antonios G., additional, Perlin, David S., additional, and Kontoyiannis, Dimitrios P., additional

Published
2017
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244. Antimicrobials Inspired by Nonribosomal Peptide Synthetase Gene Clusters

Author

Vila-Farres, Xavier, primary, Chu, John, additional, Inoyama, Daigo, additional, Ternei, Melinda A., additional, Lemetre, Christophe, additional, Cohen, Louis J., additional, Cho, Wooyoung, additional, Reddy, Boojala Vijay B., additional, Zebroski, Henry A., additional, Freundlich, Joel S., additional, Perlin, David S., additional, and Brady, Sean F., additional

Published
2017
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246. Fluconazole and Echinocandin Resistance of Candida glabrata Correlates Better with Antifungal Drug Exposure Rather than with MSH2 Mutator Genotype in a French Cohort of Patients Harboring Low Rates of Resistance

Author

Dellière, Sarah, primary, Healey, Kelley, additional, Gits-Muselli, Maud, additional, Carrara, Bastien, additional, Barbaro, Alessandro, additional, Guigue, Nicolas, additional, Lecefel, Christophe, additional, Touratier, Sophie, additional, Desnos-Ollivier, Marie, additional, Perlin, David S., additional, Bretagne, Stéphane, additional, and Alanio, Alexandre, additional

Published
2016
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248. Efficacy of humanized single large doses of caspofungin on the lethality and fungal tissue burden in a deeply neutropenic murine model against Candida albicans and Candida dubliniensis.

Author

Prépost, Eszter, Tóth, Zoltán, Perlin, David S, Gesztelyi, Rudolf, Kardos, Gábor, Kovács, Renátó, Nagy, Fruzsina, Forgács, Lajos, and Majoros, László

Subjects
CANDIDA albicans, ALEMTUZUMAB, AMPHOTERICIN B, TISSUES
Abstract

Background: Echinocandins are the first-line therapy for treatment of invasive Candida infections, but the mortality rate remains high, calling for novel strategies. Giving single larger echinocandin doses infrequently is an alternative regimen. Our aim was to test this novel approach in a neutropenic murine model. Materials and methods: We compared the in vivo efficacy of single 10 and 40 mg/kg of caspofungin (2.5× and 10× the normal humanized dose) to that of the same cumulative doses of daily 2 and 8 mg/kg doses for 5 days against 2 each of wild-type C. albicans and C. dubliniensis as well as echinocandin resistant C. albicans. As a comparator, we tested daily 1 mg/kg amphotericin B. Results: In lethality experiments, all caspofungin and amphotericin B regimens improved survival against wild-type C. albicans and C. dubliniensis clinical isolates (P<0.0001) and decreased the mean fungal kidney burdens of both species compared to controls. However, fungal kidney burden decreases were not always statistically significant, especially with single 10 or 40 mg/kg caspofungin doses. Amphotericin B was the least active drug against wild-type C. albicans. Against echinocandin-resistant strains, monodose 40 mg/kg caspofungin and 1 mg/kg of daily amphotericin B were effective in lethality experiments. Although, significant kidney CFU decreases were never found, except for amphotericin B against one of the isolates (p<0.05 at day 3 and p<0.001 at day 6). Conclusion: Single 40 mg/kg caspofungin and 1 mg/kg amphotericin B proved to be effective in the lethality experiments against wild-type and echinocandin-resistant C. albicans and wild-type C. dubliniensis. This was not always shown regarding fungal tissue burdens. Single caspofungin doses used in mice in this study are attainable in humans as well, suggesting a potential place of this dosing strategy not only in prevention but also in curative treatment of evolved invasive Candida infections. [ABSTRACT FROM AUTHOR]

Published
2019
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249. Applying host disease status biomarkers to therapeutic response monitoring in invasive aspergillosis patients.

Author

Zhao, Yanan, Nagasaki, Yoji, Paderu, Padmaja, Sugrue, Michele W, Leather, Helen L, Wingard, John R, and Perlin, David S

Abstract

One critical factor impeding successful management of invasive aspergillosis (IA) is the lack of reliable biomarkers to assess therapeutic response. We hypothesized that changes in certain host biomarkers reflect the nature of infection status and disease progression. Upon primary IA diagnosis, these disease status biomarkers can be monitored to track response to antifungal therapy and provide early markers that prognosticate likelihood of response. Herein, we analyzed serum levels of three prominent host disease status biomarkers C-reactive protein (CRP), haptoglobin (Hp), and annexin A1 (ANXA1) in IA patients during antifungal therapy. A total of 81 serial serum samples were collected at five or six different time points relative to IA diagnosis from 15 probable IA patients (10 acute leukemia [AL] and five hematopoietic stem cell transplantation [HSCT]). Of note, different biomarker profiles were observed in AL and HSCT patients, as not only levels of markers were significantly lower in HSCT patients but also more prominent interconnections among markers were observed in AL patients. Using a composite evaluation, patients were categorized as responders, nonresponders, and stable cases at last specimen. For AL responders, typical biomarker profiles were high initially but rapidly decreased for CRP and Hp post antifungal therapy, while low initial ANXA1 values were restored to normal levels after treatment. In contrast, CRP and Hp were persistently elevated whilst ANXA1 remained low throughout therapy in AL non-responders. As a pilot proof-of-concept study, our work demonstrates the great potential of using host biomarkers to monitor early therapeutic response in leukemia patients. [ABSTRACT FROM AUTHOR]

Published
2019
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250. Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic

Author

Shurtleff, Valerie W., Layton, Mark E., Parish, Craig A., Perkins, James J., Schreier, John D., Wang, Yunyi, Adam, Gregory C., Alvarez, Nadine, Bahmanjah, Soheila, Bahnck-Teets, Carolyn M., Boyce, Christopher W., Burlein, Christine, Cabalu, Tamara D., Campbell, Brian T., Carroll, Steven S., Chang, Wonsuk, de Lera Ruiz, Manuel, Dolgov, Enriko, Fay, John F., Fox, Nicholas G., Goh, Shih Lin, Hartingh, Timothy J., Hurzy, Danielle M., Kelly, Michael J., Klein, Daniel J., Klingler, Franca-Maria, Krishnamurthy, Harini, Kudalkar, Shalley, Mayhood, Todd W., McKenna, Philip M., Murray, Edward M., Nahas, Debbie, Nawrat, Christopher C., Park, Steven, Qian, Dongming, Roecker, Anthony J., Sharma, Vijeta, Shipe, William D., Su, Jing, Taggart, Robert V., Truong, Quang, Wu, Yin, Zhou, Xiaoyan, Zhuang, Ningning, Perlin, David S., Olsen, David B., Howe, John A., and McCauley, John A.

Abstract

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus’s main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.

Published
2024
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