3C-like protease explained

See also: COVID-19 drug development.

SARS coronavirus main proteinase
Ec Number:3.4.22.69
Width:258

The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease,[1] is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved sites. It is a cysteine protease and a member of the PA clan of proteases. It has a cysteine-histidine catalytic dyad at its active site and cleaves a Gln–(Ser/Ala/Gly) peptide bond.

The Enzyme Commission refers to this family as SARS coronavirus main proteinase (Mpro;). The 3CL protease corresponds to coronavirus nonstructural protein 5 (nsp5). The "3C" in the common name refers to the 3C protease (3Cpro) which is a homologous protease found in picornaviruses.

Function

The 3C-like protease is able to catalytically cleave a peptide bond between a glutamine at position P1 and a small amino acid (serine, alanine, or glycine) at position P1'. The SARS coronavirus 3CLpro can for instance self-cleave the following peptides:[2] [3] [4]

The protease is important in the processing of the coronavirus replicase polyprotein . It is the main protease in coronaviruses and corresponds to nonstructural protein 5 (nsp5).[5] It cleaves the coronavirus polyprotein at 11 conserved sites. The 3CL protease has a cysteine-histidine catalytic dyad at its active site. The sulfur of the cysteine acts as a nucleophile and the imidazole ring of the histidine as a general base.[6]

Substrate preferences for 3CL proteases (from table 2)[7]
Position Substrate preference
P5 No strong preference
P4 Small hydrophobic residues
P3 Positively charged residue
P2 High hydrophobicity and absence of beta-branch
P1 Glutamine
P1' Small residues
P2' Small residues
P3' No strong preference

Nomenclature

Alternative names provided by the EC include 3CLpro, 3C-like protease, coronavirus 3C-like protease, Mpro, SARS 3C-like protease, SARS coronavirus 3CL protease, SARS coronavirus main peptidase, SARS coronavirus main protease, SARS-CoV 3CLpro enzyme, SARS-CoV main protease, SARS-CoV Mpro and severe acute respiratory syndrome coronavirus main protease.

As a treatment target

A number of protease inhibitors are being developed targeting 3CLpro and homologous 3Cpro, including CLpro-1, GC376, rupintrivir, lufotrelvir, PF-07321332, and AG7404.[8] [9] [10] [11] [12] The intravenous administered prodrug PF-07304814 (lufotrelvir) entered clinical trials in September 2020.[13]

After clinical trials, in December 2021, the oral medication nirmatrelvir (formerly PF-07321332) became commercially available under emergency use authorizations (EUA), as part of the nirmatrelvir/ritonavir combination therapy (brand name Paxlovid).[14] [15] In May 2023, the medication got full FDA approval for high-risk adults, while children 12–18 were still covered under the EUA.[16]

The 3C-like protease inhibitor ensitrelvir received authorization to treat COVID-19 in Japan in 2022.[17] [18]

In 2022, an ultralarge virtual screening campaign of 235 million molecules was able to identify a novel broad-spectrum inhibitor targeting the main protease of several coronaviruses. It is unusually not a peptidomimetic.[19]

Other 3C(-like) proteases

3C-like proteases (3C(L)pro) are widely found in (+)ssRNA viruses. All of them are cysteine proteases with a chymotrypsin-like fold (PA clan), using a catalytic dyad or triad. They share some general similarities on substrate specificity and inhibitor effectiveness. They are divided into subfamilies by sequence similarity, corresponding to the family of viruses they are found in:[20]

Additional members are known from Potyviridae and non-Coronaviridae Nidovirales.[21]

See also

Further reading

External links

Notes and References

  1. Ahmad B, Batool M, Ain QU, Kim MS, Choi S. August 2021. Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations. International Journal of Molecular Sciences. 22. 17. 9124. 10.3390/ijms22179124. 8430524. 34502033. free.
  2. Goetz DH, Choe Y, Hansell E, Chen YT, McDowell M, Jonsson CB, Roush WR, McKerrow J, Craik CS . Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus . Biochemistry . 46 . 30 . 8744–52 . July 2007 . 17605471 . 10.1021/bi0621415 .
  3. Fan K, Wei P, Feng Q, Chen S, Huang C, Ma L, Lai B, Pei J, Liu Y, Chen J, Lai L . Biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome coronavirus 3C-like proteinase . The Journal of Biological Chemistry . 279 . 3 . 1637–42 . January 2004 . 14561748 . 10.1074/jbc.m310875200 . 7980035 . free .
  4. Akaji K, Konno H, Onozuka M, Makino A, Saito H, Nosaka K . Evaluation of peptide-aldehyde inhibitors using R188I mutant of SARS 3CL protease as a proteolysis-resistant mutant . Bioorganic & Medicinal Chemistry . 16 . 21 . 9400–8 . November 2008 . 18845442 . 10.1016/j.bmc.2008.09.057 . 7126698 .
  5. Book: Coronaviruses. Fehr AR, Perlman S. 2015. Springer. 978-1-4939-2438-7. Maier HJ, Bickerton E, Britton P. Methods in Molecular Biology. 1282. 1–23. Coronaviruses: an overview of their replication and pathogenesis. 10.1007/978-1-4939-2438-7_1. 4369385. 25720466. See section: Virion Structure..
  6. Ryu YB, Park SJ, Kim YM, Lee JY, Seo WD, Chang JS, Park KH, Rho MC, Lee WS . 6. SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii . Bioorganic & Medicinal Chemistry Letters . 20 . 6 . 1873–6 . March 2010 . 20167482 . 7127101 . 10.1016/j.bmcl.2010.01.152 . 0960-894X .
  7. Chuck CP, Chow HF, Wan DC, Wong KB . Profiling of substrate specificities of 3C-like proteases from group 1, 2a, 2b, and 3 coronaviruses . PLOS ONE . 6 . 11 . e27228 . 2011 . 22073294 . 3206940 . 10.1371/journal.pone.0027228 . 2011PLoSO...627228C . free .
  8. Tian D, Liu Y, Liang C, Xin L, Xie X, Zhang D, Wan M, Li H, Fu X, Liu H, Cao W . An update review of emerging small-molecule therapeutic options for COVID-19 . Biomedicine & Pharmacotherapy . 137 . 111313 . May 2021 . 33556871 . 7857046 . 10.1016/j.biopha.2021.111313 .
  9. Morse JS, Lalonde T, Xu S, Liu WR . Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV . ChemBioChem . 21 . 5 . 730–738 . March 2020 . 32022370 . 7162020 . 10.1002/cbic.202000047 .
  10. Liu C, Zhou Q, Li Y, Garner LV, Watkins SP, Carter LJ, Smoot J, Gregg AC, Daniels AD, Jervey S, Albaiu D . 6 . Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases . ACS Central Science . 6 . 3 . 315–331 . March 2020 . 32226821 . 10.1021/acscentsci.0c00272 . 7094090 . free .
  11. Ramajayam R, Tan KP, Liang PH . Recent development of 3C and 3CL protease inhibitors for anti-coronavirus and anti-picornavirus drug discovery . Biochemical Society Transactions . 39 . 5 . 1371–5 . October 2011 . 21936817 . 10.1042/BST0391371 .
  12. Dai W, Zhang B, Jiang XM, Su H, Li J, Zhao Y, Xie X, Jin Z, Peng J, Liu F, Li C, Li Y, Bai F, Wang H, Cheng X, Cen X, Hu S, Yang X, Wang J, Liu X, Xiao G, Jiang H, Rao Z, Zhang LK, Xu Y, Yang H, Liu H . 6. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease . Science . 368 . 6497 . 1331–1335 . June 2020 . 32321856 . 7179937 . 10.1126/science.abb4489 . 2020Sci...368.1331D. free.
  13. First-In-Human Study To Evaluate Safety, Tolerability, And Pharmacokinetics Following Single Ascending And Multiple Ascending Doses of PF-07304814 In Hospitalized Participants With COVID-19. . . 24 June 2021 . Clinical Trials . 3 July 2021.
  14. Fact sheet for healthcare providers: Emergency Use Authorization for Paxlovid . LAB-1492-0.8 . . 22 December 2021 . PDF . https://web.archive.org/web/20211223210430/https://www.fda.gov/media/155050/download . 23 December 2021 . live.
  15. Pfizer Receives U.S. FDA Emergency Use Authorization for Novel COVID-19 Oral Antiviral Treatment . . 22 December 2021 . 22 December 2021 . Business Wire . 22 December 2021 . https://web.archive.org/web/20211222175027/https://www.businesswire.com/news/home/20211221005795/en/Pfizer-Receives-U.S.-FDA-Emergency-Use-Authorization-for-Novel-COVID-19-Oral-Antiviral-Treatment . live .
  16. FDA Approves First Oral Antiviral for Treatment of COVID-19 in Adults . U.S. Food and Drug Administration (FDA) . 26 May 2023 . 26 May 2023.
  17. Xocova (Ensitrelvir Fumaric Acid) Tablets 125mg Approved in Japan for the Treatment of SARS-CoV-2 Infection, under the Emergency Regulatory Approval System . . 22 November 2022 . 28 November 2022.
  18. Web site: Lenharo . Mariana . New Pill Helps COVID Smell and Taste Loss Fade Quickly . . 18 October 2023 . 28 October 2023.
  19. Luttens A, Gullberg H, Abdurakhmanov E, Vo DD, Akaberi D, Talibov VO, Nekhotiaeva N, Vangeel L, De Jonghe S, Jochmans D, Krambrich J, Tas A, Lundgren B, Gravenfors Y, Craig AJ, Atilaw Y, Sandström A, Moodie LK, Lundkvist Å, van Hemert MJ, Neyts J, Lennerstrand J, Kihlberg J, Sandberg K, Danielson UH, Carlsson J . 6. Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses . J Am Chem Soc . 144 . 7 . 2905–2920 . February 2022 . 35142215 . 8848513 . 10.1021/jacs.1c08402 . 0002-7863.
  20. Kim Y, Lovell S, Tiew KC, Mandadapu SR, Alliston KR, Battaile KP, Groutas WC, Chang KO . 6 . Broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, noroviruses, and coronaviruses . Journal of Virology . 86 . 21 . 11754–62 . November 2012 . 22915796 . 3486288 . 10.1128/JVI.01348-12 .
  21. Ziebuhr J, Bayer S, Cowley JA, Gorbalenya AE . The 3C-like proteinase of an invertebrate nidovirus links coronavirus and potyvirus homologs . Journal of Virology . 77 . 2 . 1415–26 . January 2003 . 12502857 . 10.1128/jvi.77.2.1415-1426.2003 . 140795 . free .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "3C-like protease".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.