Rational design of a new class of protease inhibitors for the potential treatment of coronavirus diseases

Westberg, Michael; Su, Yichi; Zou, Xinzhi; Lin, Ning; Hurst, Brett L.; Tarbet, E. Bart; Lin, Michael

doi:10.1101/2020.09.15.275891

Cited by 19 publications

(25 citation statements)

References 48 publications

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“…In conclusion, inhibition of the M pro and PL pro proteases is considered to be a potentially activity in cells 26,37 . In this work, we describe our efforts to screen a library of approximately 650 diverse covalent inhibitor scaffolds against the two primary SARS-CoV-2 cysteine proteases, M pro and PL pro .…”

Section: Resultsmentioning

confidence: 94%

“…The majority of current approaches only use inhibition of viral replication as a metric for efficacy of lead molecules without any direct confirmation of target inhibition. Only recently, has inhibition of processing of a genetically expressed M pro substrate or labeling of active M pro enzyme been established as a measure of M pro activity in cells 26,37 . In this work, we describe our efforts to screen a library of approximately 650 diverse covalent inhibitor scaffolds against the two primary SARS-CoV-2 cysteine proteases, M pro and PL pro .…”

Section: Resultsmentioning

confidence: 99%

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Challenges for targeting SARS-CoV-2 proteases as a therapeutic strategy for COVID-19

Steuten

Kim

Widen

et al. 2020

Preprint

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Two proteases produced by the SARS-CoV-2 virus, Mpro and PLpro, are essential for viral replication and have become the focus of drug development programs for treatment of COVID-19. We screened a highly focused library of compounds containing covalent warheads designed to target cysteine proteases to identify new lead scaffolds for both Mpro and PLpro proteases. These efforts identified a small number of hits for the Mpro protease and no viable hits for the PLpro protease. Of the Mpro hits identified as inhibitors of the purified recombinant protease, only two compounds inhibited viral infectivity in cellular infection assays. However, we observed a substantial drop in antiviral potency upon expression of TMPRSS2, a transmembrane serine protease that acts in an alternative viral entry pathway to the lysosomal cathepsins. This loss of potency is explained by the fact that our lead Mpro inhibitors are also potent inhibitors of host cell cysteine cathepsins. To determine if this is a general property of Mpro inhibitors, we evaluated several recently reported compounds and found that they are also effective inhibitors of purified human cathepsin L and B and showed similar loss in activity in cells expressing TMPRSS2. Our results highlight the challenges of targeting Mpro and PLpro proteases and demonstrate the need to carefully assess selectivity of SARS-CoV-2 protease inhibitors to prevent clinical advancement of compounds that function through inhibition of a redundant viral entry pathway.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Challenges for targeting SARS-CoV-2 proteases as a therapeutic strategy for COVID-19

Steuten

Kim

Widen

et al. 2020

Preprint

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“…Cyclic peptide inhibitors that target viral proteins, such as the SARS-CoV-2 main protease (M pro ), may offer promise as antiviral drugs with pharmacological properties similar to cyclosporine A. M pro is one of the best-characterized drug targets for coronaviruses. 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , (b) , (c) , (d) , 40 M pro cleaves the initially translated viral polyprotein into its component proteins within cells infected by SARS-CoV-2. Cleavage generally occurs immediately after a Gln residue, and the Gln residue is typically preceded by a hydrophobic residue, most often Leu.…”

Section: Introductionmentioning

confidence: 99%

A cyclic peptide inhibitor of the SARS-CoV-2 main protease

Kreutzer

Krumberger

Diessner

et al. 2021

European Journal of Medicinal Chemistry

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“…Further, complete inhibition of infection was achieved with 100 nM N-0385 in colonoids derived from human donors confirming the low nanomolar potency of N-0385 against SARS-CoV-2. To date, GC-376, a DAA targeting 3CL pro , is the only other lead antiviral candidate for SARS-CoV-2 for which a comparable SI to N-0385 has been reported in bioRxiv 48 .…”

Section: Discussionmentioning

confidence: 99%

A novel highly potent inhibitor of TMPRSS2-like proteases blocks SARS-CoV-2 variants of concern and is broadly protective against infection and mortality in mice

Shapira

Monreal

Dion

et al. 2021

Preprint

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SummaryThe COVID-19 pandemic caused by the SARS-CoV-2 virus remains a global public health crisis. Although widespread vaccination campaigns are underway, their efficacy is reduced against emerging variants of concern (VOCs) 1,2. Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against VOCs 3,4. Attractive pharmacological targets to impede viral entry include type-II transmembrane serine proteases (TTSPs), such as TMPRSS2, whose essential role in the virus lifecycle is responsible for the cleavage and priming of the viral spike protein 5–7. Here, we identify and characterize a small-molecule compound, N-0385, as the most potent inhibitor of TMPRSS2 reported to date. N-0385 exhibited low nanomolar potency and a selectivity index of >106 at inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids 8. Importantly, N-0385 acted as a broad-spectrum coronavirus inhibitor of two SARS-CoV-2 VOCs, B.1.1.7 and B.1.351. Strikingly, single daily intranasal administration of N-0385 early in infection significantly improved weight loss and clinical outcomes, and yielded 100% survival in the severe K18-human ACE2 transgenic mouse model of SARS-CoV-2 disease. This demonstrates that TTSP-mediated proteolytic maturation of spike is critical for SARS-CoV-2 infection in vivo and suggests that N-0385 provides a novel effective early treatment option against COVID-19 and emerging SARS-CoV-2 VOCs.

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Rational design of a new class of protease inhibitors for the potential treatment of coronavirus diseases

Cited by 19 publications

References 48 publications

Challenges for targeting SARS-CoV-2 proteases as a therapeutic strategy for COVID-19

Challenges for targeting SARS-CoV-2 proteases as a therapeutic strategy for COVID-19

A cyclic peptide inhibitor of the SARS-CoV-2 main protease

A novel highly potent inhibitor of TMPRSS2-like proteases blocks SARS-CoV-2 variants of concern and is broadly protective against infection and mortality in mice

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