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F r o m W i k i p e d i a , t h e f r e e e n c y c l o p e d i a
( R e d i r e c t e d f r o m M a i n p r o t e a s e )
The 3C-like protease (3CLpro ) or main protease (M pro ), formally known as C30 endopeptidase or 3-chymotrypsin-like protease ,[2] 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 (M pro ; EC 3.4.22.69 ). 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 [ edit ]
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 :[3] [4] [5]
TSAVLQ -S GFRK-NH2 and SGVTFQ -G KFKK are the two peptides corresponding to the two self-cleavage sites of the SARS 3C-like proteinase
The protease is important in the processing of the coronavirus replicase polyprotein (P0C6U8 ). It is the main protease in coronaviruses and corresponds to nonstructural protein 5 (nsp5).[6] It cleaves the coronavirus polyprotein at 11 conserved sites. The 3CL protease has a cysteine-histidine catalytic dyad at its active site.[4] The sulfur of the cysteine acts as a nucleophile and the imidazole ring of the histidine as a general base .[7]
Substrate preferences for 3CL proteases (from table 2)[8]
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 [ edit ]
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 [ edit ]
Nirmatrelvir bound to 3CL PDB : 7RFW
Nirmatrelvir , a 3CLpro inhibitor developed by Pfizer in phase II/III clinical trials as a combination drug with ritonavir .[9] [10]
A number of protease inhibitors are being developed targeting 3CLpro and homologous 3Cpro , including CLpro-1 , GC376 , rupintrivir , lufotrelvir , PF-07321332 , and AG7404 .[11] [12] [13] [14] [1] The intravenous administered prodrug PF-07304814 (lufotrelvir) entered clinical trials in September 2020.[15]
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).[16] [17] In May 2023, the medication got full FDA approval for high-risk adults, while children 12–18 were still covered under the EUA.[18]
The 3C-like protease inhibitor ensitrelvir received authorization to treat COVID-19 in Japan in 2022.[19] [20]
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.[21]
A ligand-binding diagram showing the amino acid residues in contact with a covalently bound peptidomimetic protease inhibitor . The small red spheres are water molecules .[1]
Other 3C(-like) proteases [ edit ]
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:[22]
Additional members are known from Potyviridae and non-Coronaviridae Nidovirales .[23]
See also [ edit ]
References [ edit ]
^ Goetz DH, Choe Y, Hansell E, Chen YT, McDowell M, Jonsson CB, Roush WR, McKerrow J, Craik CS (July 2007). "Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus". Biochemistry . 46 (30 ): 8744–52. doi :10.1021/bi0621415 . PMID 17605471 .
^ a b Fan K, Wei P, Feng Q, Chen S, Huang C, Ma L, Lai B, Pei J, Liu Y, Chen J, Lai L (January 2004). "Biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome coronavirus 3C-like proteinase" . The Journal of Biological Chemistry . 279 (3 ): 1637–42. doi :10.1074/jbc.m310875200 . PMC 7980035 . PMID 14561748 .
^ Akaji K, Konno H, Onozuka M, Makino A, Saito H, Nosaka K (November 2008). "Evaluation of peptide-aldehyde inhibitors using R188I mutant of SARS 3CL protease as a proteolysis-resistant mutant" . Bioorganic & Medicinal Chemistry . 16 (21 ): 9400–8. doi :10.1016/j.bmc.2008.09.057 . PMC 7126698 . PMID 18845442 .
^ Fehr AR, Perlman S (2015). "Coronaviruses: an overview of their replication and pathogenesis". In Maier HJ, Bickerton E, Britton P (eds.). Coronaviruses . Methods in Molecular Biology. Vol. 1282. Springer. pp. 1–23. doi :10.1007/978-1-4939-2438-7_1 . ISBN 978-1-4939-2438-7 . PMC 4369385 . PMID 25720466 . See section: Virion Structure.
^ Ryu YB, Park SJ, Kim YM, Lee JY, Seo WD, Chang JS, et al. (March 2010). "SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii" . Bioorganic & Medicinal Chemistry Letters . 20 (6 ): 1873–6. doi :10.1016/j.bmcl.2010.01.152 . ISSN 0960-894X . PMC 7127101 . PMID 20167482 .
^ Chuck CP, Chow HF, Wan DC, Wong KB (2011). "Profiling of substrate specificities of 3C-like proteases from group 1, 2a, 2b, and 3 coronaviruses" . PLOS ONE . 6 (11 ): e27228. Bibcode :2011PLoSO...627228C . doi :10.1371/journal.pone.0027228 . PMC 3206940 . PMID 22073294 .
^ Vandyck K, Deval J (August 2021). "Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection" . Curr Opin Virol . 49 : 36–40. doi :10.1016/j.coviro.2021.04.006 . PMC 8075814 . PMID 34029993 .
^ "Pfizer begins dosing in Phase II/III trial of antiviral drug for Covid-19" . Clinical Trials Arena . 2 September 2021.
^ Tian D, Liu Y, Liang C, Xin L, Xie X, Zhang D, Wan M, Li H, Fu X, Liu H, Cao W (May 2021). "An update review of emerging small-molecule therapeutic options for COVID-19" . Biomedicine & Pharmacotherapy . 137 : 111313. doi :10.1016/j.biopha.2021.111313 . PMC 7857046 . PMID 33556871 .
^ Morse JS, Lalonde T, Xu S, Liu WR (March 2020). "Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV" . ChemBioChem . 21 (5 ): 730–738. doi :10.1002/cbic.202000047 . PMC 7162020 . PMID 32022370 .
^ Liu C, Zhou Q, Li Y, Garner LV, Watkins SP, Carter LJ, et al. (March 2020). "Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases" . ACS Central Science . 6 (3 ): 315–331. doi :10.1021/acscentsci.0c00272 . PMC 7094090 . PMID 32226821 .
^ Ramajayam R, Tan KP, Liang PH (October 2011). "Recent development of 3C and 3CL protease inhibitors for anti-coronavirus and anti-picornavirus drug discovery". Biochemical Society Transactions . 39 (5 ): 1371–5. doi :10.1042/BST0391371 . PMID 21936817 .
^ "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" . Clinical Trials . 24 June 2021. Retrieved 3 July 2021 .
^ Fact sheet for healthcare providers: Emergency Use Authorization for Paxlovid (PDF) (Technical report). Pfizer . 22 December 2021. LAB-1492-0.8. Archived from the original on 23 December 2021.
^ "Pfizer Receives U.S. FDA Emergency Use Authorization for Novel COVID-19 Oral Antiviral Treatment" (Press release). Pfizer . 22 December 2021. Archived from the original on 22 December 2021. Retrieved 22 December 2021 – via Business Wire.
^ "FDA Approves First Oral Antiviral for Treatment of COVID-19 in Adults" . U.S. Food and Drug Administration (FDA) (Press release). 26 May 2023. Retrieved 26 May 2023 . This article incorporates text from this source, which is in the public domain .
^ "Xocova (Ensitrelvir Fumaric Acid) Tablets 125mg Approved in Japan for the Treatment of SARS-CoV-2 Infection, under the Emergency Regulatory Approval System" . Shionogi (Press release). 22 November 2022. Retrieved 28 November 2022 .
^ Lenharo, Mariana (18 October 2023). "New Pill Helps COVID Smell and Taste Loss Fade Quickly" . Scientific American . Retrieved 28 October 2023 .
^ Luttens A, Gullberg H, Abdurakhmanov E, Vo DD, Akaberi D, Talibov VO, et al. (February 2022). "Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses" . J Am Chem Soc . 144 (7 ): 2905–2920. doi :10.1021/jacs.1c08402 . ISSN 0002-7863 . PMC 8848513 . PMID 35142215 .
^ Kim Y, Lovell S, Tiew KC, Mandadapu SR, Alliston KR, Battaile KP, et al. (November 2012). "Broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, noroviruses, and coronaviruses" . Journal of Virology . 86 (21 ): 11754–62. doi :10.1128/JVI.01348-12 . PMC 3486288 . PMID 22915796 .
^ Ziebuhr J, Bayer S, Cowley JA, Gorbalenya AE (January 2003). "The 3C-like proteinase of an invertebrate nidovirus links coronavirus and potyvirus homologs" . Journal of Virology . 77 (2 ): 1415–26. doi :10.1128/jvi.77.2.1415-1426.2003 . PMC 140795 . PMID 12502857 .
Further reading [ edit ]
External links [ edit ]
R e t r i e v e d f r o m " https://en.wikipedia.org/w/index.php?title=3C-like_protease&oldid=1224249053 "
C a t e g o r i e s :
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● A r t i c l e s w i t h s h o r t d e s c r i p t i o n
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● T h i s p a g e w a s l a s t e d i t e d o n 1 7 M a y 2 0 2 4 , a t 0 5 : 0 4 ( U T C ) .
● T e x t i s a v a i l a b l e u n d e r t h e C r e a t i v e C o m m o n s A t t r i b u t i o n - S h a r e A l i k e L i c e n s e 4 . 0 ;
a d d i t i o n a l t e r m s m a y a p p l y . B y u s i n g t h i s s i t e , y o u a g r e e t o t h e T e r m s o f U s e a n d P r i v a c y P o l i c y . W i k i p e d i a ® i s a r e g i s t e r e d t r a d e m a r k o f t h e W i k i m e d i a F o u n d a t i o n , I n c . , a n o n - p r o f i t o r g a n i z a t i o n .
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