Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV)

Dampalla, Chamandi S.; Miller, Matthew J.; Kim, Yunjeong; Zabiegala, Alexandria; Nguyen, Harry Nhat; Madden, Trent K.; Thurman, Hayden A.; Machen, Alexandra J.; Cooper, Anne; Liu, Lijun; Battaile, Kevin P.; Lovell, Scott; Chang, Kyeong-Ok; Groutas, William C.

doi:10.1016/j.ejmech.2023.115376

Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV)

Journal Article · Sat Apr 15 00:00:00 EDT 2023 · European Journal of Medicinal Chemistry

DOI:https://doi.org/10.1016/j.ejmech.2023.115376· OSTI ID:2423799

^[1]; Miller, Matthew J. ^[1]; Kim, Yunjeong ^[2]; Zabiegala, Alexandria ^[2]; Nguyen, Harry Nhat ^[1]; Madden, Trent K. ^[1]; Thurman, Hayden A. ^[1]; Machen, Alexandra J. ^[3]; Cooper, Anne ^[3]; Liu, Lijun ^[3]; Battaile, Kevin P. ^[4]; Lovell, Scott ^[3]; Chang, Kyeong-Ok ^[2]; Groutas, William C. ^[1]

Wichita State Univ., Wichita, KS (United States)
Kansas State Univ., Manhattan, KS (United States)
Univ. of Kansas, Lawrence, KS (United States)
New York Structural Biology Center (NYSBC), Upton, NY (United States)

The high morbidity and mortality associated with SARS-CoV-2 infection, the etiological agent of COVID-19, has had a major impact on global public health. Significant progress has been made in the development of an array of vaccines and biologics, however, the emergence of SARS-CoV-2 variants and breakthrough infections are an ongoing major concern. Furthermore, there is an existing paucity of small-molecule host and virus-directed therapeutics and prophylactics that can be used to counter the spread of SARS-CoV-2, and any emerging and re-emerging coronaviruses. Here, we describe herein our efforts to address this urgent need by focusing on the structure-guided design of potent broad-spectrum inhibitors of SARS-CoV-2 3C-like protease (3CL^pro or Main protease), an enzyme essential for viral replication. The inhibitors exploit the directional effects associated with the presence of a gem-dimethyl group that allow the inhibitors to optimally interact with the S4 subsite of the enzyme. Several compounds were found to potently inhibit SARS-CoV-2 and MERS-CoV 3CL proteases in biochemical and cell-based assays. Specifically, the EC50 values of aldehyde 1c and its corresponding bisulfite adduct 1d against SARS-CoV-2 were found to be 12 and 10 nM, respectively, and their CC50 values were >50 μM. Furthermore, deuteration of these compounds yielded compounds 2c/2d with EC50 values 11 and 12 nM, respectively. Replacement of the aldehyde warhead with a nitrile (CN) or an α-ketoamide warhead or its corresponding bisulfite adduct yielded compounds 1g, 1e and 1f with EC50 values 60, 50 and 70 nM, respectively. High-resolution cocrystal structures have identified the structural determinants associated with the binding of the inhibitors to the active site of the enzyme and, furthermore, have illuminated the mechanism of action of the inhibitors. Overall, the high Safety Index (SI) (SI=CC50/EC50) displayed by these compounds suggests that they are well-suited to conducting further preclinical studies.

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Research Organization:: Brookhaven Science Associates, LLC, Upton, NY (United States); UChicago Argonne, LLC, Chicago, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation (NSF); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-06CH11357; SC0012704

OSTI ID:: 2423799

Alternate ID(s):: OSTI ID: 1970422

Journal Information:: European Journal of Medicinal Chemistry, Journal Name: European Journal of Medicinal Chemistry Journal Issue: C Vol. 254; ISSN 0223-5234

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
Broad-spectrum inhibitors
Coronavirus
MERS-CoV
Pharmacology & Pharmacy
SARS-CoV-2
gem-dimethyl effect

Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV)

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References (76)

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