DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 M pro inhibitors.
Srinivas Chamakuri,Shuo Lu,Melek N. Ucisik,Kurt M. Bohren,Ying-Chu Chen,Huang-Chi Du,John C. Faver,Ravikumar Jimmidi,Feng Li,J. Li,Pranavanand Nyshadham,Stephen Palmer,Jeroen Pollet,Jeroen Pollet,Xuan Qin,Shannon E. Ronca,Banumathi Sankaran,Kiran L. Sharma,Zhi Tan,Leroy Versteeg,Leroy Versteeg,Zhifeng Yu,Martin M. Matzuk,Timothy Palzkill,Damian W. Young +24 more
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TLDR
In this paper, an affinity-based screen of 4 billion DNA-encoded molecules en masse was used to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro).Abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition constant [K i] = 20 nM). CDD-1713, a smaller two-building-block analog (MW = 353.3 g/mol) of CDD-1714, is a reversible covalent inhibitor of Mpro (K i = 45 nM) that binds in the protease pocket, has specificity over human proteases, and shows in vitro efficacy in a SARS-CoV-2 infectivity model. Subsequently, key regions of CDD-1713 that were necessary for inhibitory activity were identified and a potent (K i = 37 nM), smaller (MW = 323.4 g/mol), and metabolically more stable analog (CDD-1976) was generated. Thus, screening of DNA-encoded chemical libraries can accelerate the discovery of efficacious drug-like inhibitors of emerging viral disease targets.read more
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Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors
Seyed Arad Moghadasi,Emmanuel Heilmann,Ahmed Magdy Khalil,Christina Nnabuife,Fiona L. Kearns,Chengjin Ye,Sofia N. Moraes,Francesco Costacurta,Morgan A. Esler,Hideki Aihara,Dorothee von Laer,Luis Martinez-Sobrido,Timothy Palzkill,Rommie E. Amaro,Reuben S. Harris +14 more
TL;DR: Investigation of the susceptibility of natural variants of the main protease of SARS-CoV-2 to protease inhibitors indicates that nirmatrelvir-resisting variants have pre-existed the introduction of this drug into the human population and are capable of spreading.
Journal ArticleDOI
Non-covalent SARS-CoV-2 Mpro inhibitors developed from in silico screen hits
Giacomo G. Rossetti,Maria Angeles Mayo Ossorio,Stephan Rempel,Annika Kratzel,Vasilis S. Dionellis,Samia Barriot,Laurence Tropia,Christoph Gorgulla,Haribabu Arthanari,Volker Thiel,Peter Mohr,Remo Gamboni,Thanos D. Halazonetis +12 more
TL;DR: In this article , the main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified and two interesting chemotypes were identified, which were further evaluated by characterizing an additional five hundred synthesis on-demand analogues.
Journal ArticleDOI
Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors
Seyed Arad Moghadasi,Emmanuel Heilmann,Ahmed Magdy Khalil,Christina Nnabuife,Fiona L. Kearns,Chengjin Ye,Sofia N. Moraes,Francesco Costacurta,Morgan A. Esler,Hideki Aihara,Dorothee von Laer,Luis Martinez-Sobrido,Timothy Palzkill,Rommie E. Amaro,Reuben S. Harris +14 more
TL;DR: In this article , the authors investigate the susceptibility of natural variants of the main protease [Mpro; 3C-like protease (3CLpro)] of SARS-CoV-2 to protease inhibitors.
Journal ArticleDOI
Visible Light-Promoted Divergent Benzoheterocyclization from Aldehydes for DNA-Encoded Chemical Libraries.
TL;DR: A visible light-promoted divergent synthesis of on-DNA benzoheterocycles from aldehydes is presented, demonstrating the feasibility of this approach in DNA-encoded chemical library construction.
Journal ArticleDOI
Gain-of-Signal Assays for Probing Inhibition of SARS-CoV-2 Mpro/3CLpro in Living Cells
Seyed Arad Moghadasi,Morgan A. Esler,Yuka Otsuka,Jordan T. Becker,Sofia N. Moraes,Constance B. Anderson,Srinivas Chamakuri,Christopher Belica,Chloe Wick,Daniel A. Harki,Damian W. Young,Louis Scampavia,Timothy P. Spicer,Ke Shi,Hideki Aihara,William L. Brown,Reuben S. Harris +16 more
TL;DR: These systems rapidly, safely, and sensitively identify Mpro variants with altered susceptibilities to inhibition, triage-nonspecific, or off-target molecules and validate bona fide inhibitors, with the most potent thus far being the first-in-class drug nirmatrelvir.
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