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Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases.
Scheme 1
Fig. 1
Chuck CP, Chen C, Ke Z, Wan DC, Chow HF, Wong KB
OpenAccess logo Eur J Med Chem 59 1-6 (2013)
Related entries: 3vb3, 3vb4, 3vb6, 3vb7

Cited: 46 times
EuropePMC logo PMID: 23202846

Abstract

Coronaviral infection is associated with up to 5% of respiratory tract diseases. The 3C-like protease (3CL(pro)) of coronaviruses is required for proteolytic processing of polyproteins and viral replication, and is a promising target for the development of drugs against coronaviral infection. We designed and synthesized four nitrile-based peptidomimetic inhibitors with different N-terminal protective groups and different peptide length, and examined their inhibitory effect on the in-vitro enzymatic activity of 3CL(pro) of severe-acute-respiratory-syndrome-coronavirus. The IC(50) values of the inhibitors were in the range of 4.6-49 μM, demonstrating that the nitrile warhead can effectively inactivate the 3CL(pro) autocleavage process. The best inhibitor, Cbz-AVLQ-CN with an N-terminal carbobenzyloxy group, was ~10x more potent than the other inhibitors tested. Crystal structures of the enzyme-inhibitor complexes showed that the nitrile warhead inhibits 3CL(pro) by forming a covalent bond with the catalytic Cys145 residue, while the AVLQ peptide forms a number of favourable interactions with the S1-S4 substrate-binding pockets. We have further showed that the peptidomimetic inhibitor, Cbz-AVLQ-CN, has broad-spectrum inhibition against 3CL(pro) from human coronavirus strains 229E, NL63, OC43, HKU1, and infectious bronchitis virus, with IC(50) values ranging from 1.3 to 3.7 μM, but no detectable inhibition against caspase-3. In summary, we have shown that the nitrile-based peptidomimetic inhibitors are effective against 3CL(pro), and they inhibit 3CL(pro) from a broad range of coronaviruses. Our results provide further insights into the future design of drugs that could serve as a first line defence against coronaviral infection.

Reviews - 3vb5 mentioned but not cited (5)

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  3. Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CLpro). Han SH, Goins CM, Arya T, Shin WJ, Maw J, Hooper A, Sonawane DP, Porter MR, Bannister BE, Crouch RD, Lindsey AA, Lakatos G, Martinez SR, Alvarado J, Akers WS, Wang NS, Jung JU, Macdonald JD, Stauffer SR. J Med Chem 65 2880-2904 (2022)
  4. Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease. Kneller DW, Li H, Phillips G, Weiss KL, Zhang Q, Arnould MA, Jonsson CB, Surendranathan S, Parvathareddy J, Blakeley MP, Coates L, Louis JM, Bonnesen PV, Kovalevsky A. Nat Commun 13 2268 (2022)
  5. Coronaviruses resistant to a 3C-like protease inhibitor are attenuated for replication and pathogenesis, revealing a low genetic barrier but high fitness cost of resistance. Deng X, StJohn SE, Osswald HL, O'Brien A, Banach BS, Sleeman K, Ghosh AK, Mesecar AD, Baker SC. J Virol 88 11886-11898 (2014)
  6. Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors. Shimamoto Y, Hattori Y, Kobayashi K, Teruya K, Sanjoh A, Nakagawa A, Yamashita E, Akaji K. Bioorg Med Chem 23 876-890 (2015)
  7. Synthesis, modification and docking studies of 5-sulfonyl isatin derivatives as SARS-CoV 3C-like protease inhibitors. Liu W, Zhu HM, Niu GJ, Shi EZ, Chen J, Sun B, Chen WQ, Zhou HG, Yang C. Bioorg Med Chem 22 292-302 (2014)
  8. Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir. Lo HS, Hui KPY, Lai HM, He X, Khan KS, Kaur S, Huang J, Li Z, Chan AKN, Cheung HH, Ng KC, Ho JCW, Chen YW, Ma B, Cheung PM, Shin D, Wang K, Lee MH, Selisko B, Eydoux C, Guillemot JC, Canard B, Wu KP, Liang PH, Dikic I, Zuo Z, Chan FKL, Hui DSC, Mok VCT, Wong KB, Mok CKP, Ko H, Aik WS, Chan MCW, Ng WL. ACS Cent Sci 7 792-802 (2021)
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