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Label-free duplex SAMDI-MS screen reveals novel SARS-CoV-2 3CLpro inhibitors.

ABSTRACT: The 3-chymotrypsin-like cysteine protease (3CLpro) of severe acute respiratory syndrome conoravirus 2 (SARS-CoV-2) remains a promising therapeutic target to combat COVID-19. Our group recently described a novel duplexed biochemical assay that combines self-assembled monolayers of alkanethiolates on gold with matrix assisted laser desorption ionization (MALDI) time of flight (TOF) mass spectrometry (MS) to simultaneously measure 3CLpro and human rhinovirus 3C protease activities. This study describes applying the assay for the completion of a high-throughput duplexed screen of 300,000 diverse, drug-like small molecules in 3 days. The hits were confirmed and evaluated in dose response analyses against recombinant 3CLpro, HRV3C, and the human Cathepsin L proteases. The 3CLpro specific inhibitors were further assessed for activity in cellular cytotoxicity and anti-viral assays. Structure activity relationship studies informed on structural features required for activity and selectivity to 3CLpro over HRV3C. These results will guide the optimization of 3CLpro selective inhibitors to combat COVID-19 along with antiviral compounds against coronaviruses and rhinoviruses.

SUBMITTER: Scholle MD

PROVIDER: S-EPMC8906060 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Label-free duplex SAMDI-MS screen reveals novel SARS-CoV-2 3CLpro inhibitors.

Scholle Michael D MD O'Kane Patrick T PT Dib Sandra S Gurard-Levin Zachary A ZA

Antiviral research 20220309

The 3-chymotrypsin-like cysteine protease (3CLpro) of severe acute respiratory syndrome conoravirus 2 (SARS-CoV-2) remains a promising therapeutic target to combat COVID-19. Our group recently described a novel duplexed biochemical assay that combines self-assembled monolayers of alkanethiolates on gold with matrix assisted laser desorption ionization (MALDI) time of flight (TOF) mass spectrometry (MS) to simultaneously measure 3CLpro and human rhinovirus 3C protease activities. This study descr ...[more]

PMID: 35278580

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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic betacoronaviruses that continue to have a significant impact on public health. Timely development and introduction of vaccines and antivirals against SARS-CoV-2 into the clinic have substantially mitigated the burden of COVID-19. However, a limited or lacking therapeutic arsenal for SARS-CoV-2 and MERS-CoV infections, respectively, calls for an expanded and diversified portfolio of antivirals against these coronavirus infections. In this report, we examined the efficacy of two potent 3CLpro inhibitors, 5d and 11d, in fatal animal models of SARS-CoV-2 and MERS-CoV to demonstrate their broad-spectrum activity against both viral infections. These compounds significantly increased the survival of mice in both models when treatment started 1 day post infection compared to no treatment which led to 100% fatality. Especially, the treatment with compound 11d resulted in 80% and 90% survival in SARS-CoV-2 and MERS-CoV-infected mice, respectively. Amelioration of lung viral load and histopathological changes in treated mice correlated well with improved survival in both infection models. Furthermore, compound 11d exhibited significant antiviral activities in K18-hACE2 mice infected with SARS-CoV-2 Omicron subvariant XBB.1.16. The results suggest that these are promising candidates for further development as broad-spectrum direct-acting antivirals against highly virulent human coronaviruses.IMPORTANCEHuman coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) continue to have a significant impact on public health. A limited or lacking therapeutic arsenal for SARS-CoV-2 and MERS-CoV infections calls for an expanded and diversified portfolio of antivirals against these coronavirus infections. We have previously reported a series of small-molecule 3C-like protease (3CLpro) inhibitors against human coronaviruses. In this report, we demonstrated the in vivo efficacy of 3CLpro inhibitors for their broad-spectrum activity against both SARS-CoV-2 and MERS-CoV infections using the fatal animal models. The results suggest that these are promising candidates for further development as broad-spectrum direct-acting antivirals against highly virulent human coronaviruses.

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Label-free duplex SAMDI-MS screen reveals novel SARS-CoV-2 3CLpro inhibitors.

Publications

Label-free duplex SAMDI-MS screen reveals novel SARS-CoV-2 3CLpro inhibitors.

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