3CLp dimer binds 3CLp inhibitors

Stable Identifier
R-HSA-9694592
Type
Reaction [uncertain]
Species
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
Compartment
cytosol
Synonyms
3C-like proteinase dimer binds 3CLp inhibitors
ReviewStatus
5/5
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3CLp dimer binds 3CLp inhibitors
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The rep proteases that are essential for viral polyprotein processing by the coronaviruses and enteroviruses exhibit a strong preference for substrates containing Gln at P1 position, and share an active-site conformation that engages the substrate's P1 residue. PF-00835231, compound 11r and compound 13b are peptidomimetic α-ketoamides that function as high-affinity non-cleavable substrate analogues and thus exhibit antiviral activity against dimeric 3C-like proteinases (3CLp dimer) of coronaviruses and enteroviruses (Chen et al. 2005, Zhang et al. 2020). Nirmatrelvir contains the amide as part of a heterocycle and is optimized for oral delivery (Vandyck & Deval, 2021).

The clinical safety and efficacy of α-ketoamides in Covid-19 are under investigation. The compound PF-00835231 is in a phase I trial NCT04535167 (as phosphate prodrug), and nirmatrelvir was the subject of the phase I trial NCT04756531 that showed plasma concentrations were considerably above the SARS-COV-2 antiviral EC90 value (Owen et al, 2021). In the followup phase 2/3 trial (NCT04960202) interim analysis the drug was found to reduce the risk of hospitalization or death by 89% compared to placebo. This lead to emergency approval of the combination with ritonavir as Paxlovid.

In addition to α-ketoamides other compounds inhibit 3C-like proteinases.

Boceprevir, narlaprevir, simeprevir, telaprevir and vaniprevir are hepatitis C drugs that inhibit HCV nsp3 protease, as well as SARS-CoV-2 3CLp (Ma et al, 2020; Lo et al, 2020; Anson et al, 2020; Kneller et al, 2020; Bafna et al, 2021; Jan et al, 2021). Nelfinavir is an HIV protease inhibitor that also inhibits nsp3 at IC50 of 118 ± 18 µM (Jan et al, 2021). However, nelfinavir mesylate exhibited 15-fold higher anti–SARS-CoV-2 activity than boceprevir due to Spike inhibition (Musarrat et al, 2020).

Suramin is used to treat African sleeping sickness and river blindness, the mechanism of which is not clear. It inhibits nsp3 at an IC50 of 6.5 μM (Zhu et al, 2020). Baicalin and baicalein are natural flavonoids from Scutellaria species, used in folklore medicine and were investigated in phase I trials. They inhibit nsp3 at IC50 of 6.41 ± 0.95 µM, and 0.94 ± 0.20 µM respectively (Su et al, 2020). Ebselen is a mimic of glutathione peroxidase with antioxidant activity. In two studies inhibition of SARS-CoV-2 PLpro protease (nsp3) and 3CLp was shown. This was not confirmed, however, in a third study (Jin et al, 2020; Tomczak et al, 2021; Gurard-Levin et al, 2020).
Literature References
PubMed ID Title Journal Year
33152262 Malleability of the SARS-CoV-2 3CL Mpro Active-Site Cavity Facilitates Binding of Clinical Antivirals

Kovalevsky, A, O'Neill, HM, Kneller, DW, Phillips, G, Coates, L, Galanie, S

Structure 2020
34726479 An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19

Greasley, SE, Singh, RSP, Aschenbrenner, L, Eng, H, Updyke, L, Obach, RS, Hurst, BL, Wei, L, Sathish, JG, Kalgutkar, AS, Boras, B, Lee, J, Cardin, RD, Zhu, Y, Stewart, AE, Kadar, EP, Verhoest, PR, Ogilvie, K, Steppan, CM, Reese, MR, Noell, S, Ferre, R, Avery, M, Allerton, CMN, Sammons, MF, Di, L, Berritt, S, Yang, Q, Coffman, KJ, Mason, SW, Tuttle, JB, Gibson, SA, Rai, DK, Patel, NC, Novak, JJ, Gajiwala, KS, Owen, DR, Lee, JC, Dantonio, A, Anderson, AS, Liu, W, Carlo, A, Pettersson, M

Science 2021
32541865 Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease

Sacco, MD, Marty, MT, Chen, Y, Townsend, JA, Wang, J, Zhang, X, Hu, Y, Hurst, B, Ma, C, Szeto, T, Tarbet, B

Cell Res 2020
34075346 Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir

Canard, B, Wong, KB, Guillemot, JC, Wu, KP, Chen, YW, Ko, H, Dikic, I, Mok, VCT, Liang, PH, Chan, MCW, Cheung, PM, Hui, DSC, Aik, WS, Chan, FKL, Li, Z, Mok, CKP, Wang, K, Huang, J, Kaur, S, Cheung, HH, Chan, AKN, Eydoux, C, Zuo, Z, Shin, D, Ng, WL, Lee, MH, Khan, KS, Lai, HM, Ma, B, Ng, KC, Selisko, B, He, X, Ho, JCW, Lo, HS, Hui, KPY

ACS Cent Sci 2021
33984267 Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture

Krug, RM, García-Sastre, A, Moreno, E, Miorin, L, Kehrer, T, Royer, CA, Ramelot, TA, White, K, Bafna, K, Montelione, GT, Rosales, R, Acton, TB, Harish, B

Cell Rep 2021
  Broad-spectrum inhibition of coronavirus main and papain-like proteases by HCV drugs

Anson, BJ, D'Aquila, RT, Lendy, EK, Chapman, ME, Pshenychnyi, S, Satchell, KJF, Mesecar, AD

   
32896566 Evaluation of SARS-CoV-2 3C-like protease inhibitors using self-assembled monolayer desorption ionization mass spectrometry

Raboisson, P, Jaisinghani, R, Symons, JA, Beigelman, L, Neyts, J, Vandyck, K, Leyssen, P, Ren, S, Blatt, LM, Liu, C, Deval, J, Jochmans, D, Scholle, MD, Jekle, A, Gurard-Levin, ZA

Antiviral Res 2020
34029993 Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection

Deval, J, Vandyck, K

Curr Opin Virol 2021
32374457 The anti-HIV drug nelfinavir mesylate (Viracept) is a potent inhibitor of cell fusion caused by the SARSCoV-2 spike (S) glycoprotein warranting further evaluation as an antiviral against COVID-19 infections

Dahal, A, Chouljenko, V, Kousoulas, KG, Musarrat, F, Jois, SD, Nabi, R, Chouljenko, T

J Med Virol 2020
15507456 Severe acute respiratory syndrome coronavirus 3C-like proteinase N terminus is indispensable for proteolytic activity but not for enzyme dimerization. Biochemical and thermodynamic investigation in conjunction with molecular dynamics simulations

Chen, S, Shen, X, Chen, L, Tan, J, Jiang, H, Du, L, Chen, K, Shen, J, Sun, T, Chen, J

J. Biol. Chem. 2005
32272481 Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

Duan, Y, Zhang, L, Jin, Z, Jiang, R, Shi, Z, Deng, Y, Qin, C, Zhang, B, Yang, H, Wang, L, Xu, Y, Liu, H, You, T, Du, X, Peng, C, Liu, M, Liu, X, Xu, W, Yang, X, Yang, X, Liu, F, Li, X, Rao, Z, Xiao, G, Zhao, Y, Jiang, H, Liu, X, Bai, F, Yu, J, Yang, K, Guddat, LW

Nature 2020
32737471 Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients

Xie, H, Ke, CQ, Wang, DW, Gao, MN, Hu, HC, Ni, L, Jiang, HL, Yao, S, Bai, F, Yu, KQ, Shang, WJ, Ye, Y, Zhao, WF, Xiao, GF, Zhang, LK, Liu, H, Wu, Y, Liu, J, Xu, YC, Tang, W, Su, HX, Zuo, JP, Li, MJ, Shen, JS

Acta Pharmacol Sin 2020
32045235 α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment

Hilgenfeld, R, Wang, J, von Brunn, A, Neyts, J, Zhang, L, Leyssen, P, Snijder, EJ, Lanko, K, Kusov, Y, Liu, H, Ma, Q, Nian, Y, de Wilde, A, Lin, D

J. Med. Chem. 2020
33452205 Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection

Wu, YT, Yang, WB, Chein, RJ, Cheng, WC, Ma, C, Ma, HH, Chen, X, Hung, SC, Chou, TH, Wong, CH, Mao, SS, Liang, PH, Cheng, TR, Jan, JT, Shie, JJ, Juang, YP, Cheng, CW

Proc Natl Acad Sci U S A 2021
33062953 Identification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-Throughput Screening

Hu, X, Chen, CZ, Zheng, W, Klumpp-Thomas, C, Guo, H, Xu, M, Shen, M, Zhu, W, Shinn, P, Michael, SG

ACS Pharmacol Transl Sci 2020
Participants
Input
Output
Participates
as an event of
Disease
Name Identifier Synonyms
COVID-19 DOID:0080600 2019 Novel Coronavirus (2019-nCoV), Wuhan seafood market pneumonia virus infection, 2019-nCoV infection, Wuhan coronavirus infection
Authored
Jassal, B  (2020-04-02)
Reviewed
Acencio, ML  (2020-09-09)
Created
Cook, J  (2020-07-07)
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