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2000
Volume 22, Issue 8
  • ISSN: 1570-193X
  • E-ISSN: 1875-6298

Abstract

SARS-CoV-2 infection was first spotted in Wuhan, China and rapidly spread over the globe, causing an emergency pandemic situation. COVID-19 infection affected 773,449,299 individuals, resulting in the unfortunate loss of 6,991,842 lives. Despite the rapid development of various vaccines, there remains a significant need for antiviral drugs to effectively lower the viral load. While Receptor Binding Domain (RBD) has been identified as a potential drug target against SARS-CoV-2, the main obstacle lies in the rapid mutation of the RBD in the spike protein. The main Protease (Mpro) of SARS-CoV-2 plays a crucial role in the replication of the virus and serves as a promising drug target due to its resistance to mutation. Peptidomimetics are excellent candidates to target the main protease through the covalent attachment with its active site, thus acting as a potential inhibitor against SARS-CoV-2. This review article includes the designed principles and inhibition mechanism of the reported peptidomimetics against Mpro of SARS-CoV-2.

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2025-04-09
2025-10-14

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References

  1. SteinhauerD.A. HollandJ.J. Direct method for quantitation of extreme polymerase error frequencies at selected single base sites in viral RNA.J. Virol.198657121922810.1128/jvi.57.1.219‑228.1986 3001347
     [Google Scholar]
  2. ZhouP. YangX.L. WangX.G. HuB. ZhangL. ZhangW. SiH.R. ZhuY. LiB. HuangC.L. ChenH.D. ChenJ. LuoY. GuoH. JiangR.D. LiuM.Q. ChenY. ShenX.R. WangX. ZhengX.S. ZhaoK. ChenQ.J. DengF. LiuL.L. YanB. ZhanF.X. WangY.Y. XiaoG.F. ShiZ.L. A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature2020579779827027310.1038/s41586‑020‑2012‑7 32015507
     [Google Scholar]
  3. WuF. ZhaoS. YuB. ChenY.M. WangW. SongZ.G. HuY. TaoZ.W. TianJ.H. PeiY.Y. YuanM.L. ZhangY.L. DaiF.H. LiuY. WangQ.M. ZhengJ.J. XuL. HolmesE.C. ZhangY.Z. A new coronavirus associated with human respiratory disease in China.Nature2020579779826526910.1038/s41586‑020‑2008‑3 32015508
     [Google Scholar]
  4. YangH. XieW. XueX. YangK. MaJ. LiangW. ZhaoQ. ZhouZ. PeiD. ZiebuhrJ. HilgenfeldR. YuenK.Y. WongL. GaoG. ChenS. ChenZ. MaD. BartlamM. RaoZ. Follow the money-the politics of embryonic stem cell research.PLoS Biol.20053e23410.1371/journal.pbio.0030234 16000020
     [Google Scholar]
  5. BachaU. BarrilaJ. Velazquez-CampoyA. LeavittS.A. FreireE. Identification of novel inhibitors of the SARS coronavirus main protease 3CLpro.Biochemistry200443174906491210.1021/bi0361766 15109248
     [Google Scholar]
  6. VanommeslaegheK. HatcherE. AcharyaC. KunduS. ZhongS. ShimJ. DarianE. GuvenchO. LopesP. VorobyovI. MackerellA.D.Jr CHARMM general force field: A force field for drug‐like molecules compatible with the CHARMM all‐atom additive biological force fields.J. Comput. Chem.201031467169010.1002/jcc.21367 19575467
     [Google Scholar]
  7. BlanchardJ.E. EloweN.H. HuitemaC. FortinP.D. CechettoJ.D. EltisL.D. BrownE.D. High-throughput screening identifies inhibitors of the SARS coronavirus main proteinase.Chem. Biol.200411101445145310.1016/j.chembiol.2004.08.011 15489171
     [Google Scholar]
  8. JainR.P. PetterssonH.I. ZhangJ. AullK.D. FortinP.D. HuitemaC. EltisL.D. ParrishJ.C. JamesM.N.G. WishartD.S. VederasJ.C. Synthesis and evaluation of keto-glutamine analogues as potent inhibitors of severe acute respiratory syndrome 3CLpro.J. Med. Chem.200447256113611610.1021/jm0494873 15566280
     [Google Scholar]
  9. KaoR.Y. TsuiW.H.W. LeeT.S.W. TannerJ.A. WattR.M. HuangJ.D. HuL. ChenG. ChenZ. ZhangL. HeT. ChanK.H. TseH. ToA.P.C. NgL.W.Y. WongB.C.W. TsoiH.W. YangD. HoD.D. YuenK.Y. Identification of novel small-molecule inhibitors of severe acute respiratory syndrome-associated coronavirus by chemical genetics.Chem. Biol.20041191293129910.1016/j.chembiol.2004.07.013 15380189
     [Google Scholar]
  10. TannerJ.A. ZhengB.J. ZhouJ. WattR.M. JiangJ.Q. WongK.L. LinY.P. LuL.Y. HeM.L. KungH.F. KeselA.J. HuangJ.D. The adamantane-derived bananins are potent inhibitors of the helicase activities and replication of SARS coronavirus.Chem. Biol.200512330331110.1016/j.chembiol.2005.01.006 15797214
     [Google Scholar]
  11. WuC.Y. JanJ.T. MaS.H. KuoC.J. JuanH.F. ChengY.S.E. HsuH.H. HuangH.C. WuD. BrikA. LiangF.S. LiuR.S. FangJ.M. ChenS.T. LiangP.H. WongC.H. Small molecules targeting severe acute respiratory syndrome human coronavirus.Proc. Natl. Acad. Sci. USA200410127100121001710.1073/pnas.0403596101 15226499
     [Google Scholar]
  12. XueX. YuH. YangH. XueF. WuZ. ShenW. LiJ. ZhouZ. DingY. ZhaoQ. ZhangX.C. LiaoM. BartlamM. RaoZ. Structures of two coronavirus main proteases: Implications for substrate binding and antiviral drug design.J. Virol.20088252515252710.1128/JVI.02114‑07 18094151
     [Google Scholar]
  13. RenZ. YanL. ZhangN. GuoY. YangC. LouZ. RaoZ. The newly emerged SARS-Like coronavirus HCoV-EMC also has an “Achilles’ heel”: Current effective inhibitor targeting a 3C-like protease.Protein Cell20134424825010.1007/s13238‑013‑2841‑3 23549610
     [Google Scholar]
  14. WangF. ChenC. TanW. YangK. YangH. Population prevalence of edentulism and its association with depression and self-rated health.Sci. Rep.201663708310.1038/srep37083 27853193
     [Google Scholar]
  15. HegyiA. ZiebuhrJ. Conservation of substrate specificities among coronavirus main proteases.J. Gen. Virol.200283359559910.1099/0022‑1317‑83‑3‑595 11842254
     [Google Scholar]
  16. WuA. WangY. ZengC. HuangX. XuS. SuC. WangM. ChenY. GuoD. Prediction and biochemical analysis of putative cleavage sites of the 3C-like protease of Middle East respiratory syndrome coronavirus.Virus Res.2015208566510.1016/j.virusres.2015.05.018 26036787
     [Google Scholar]
  17. FehrA.R. PerlmanS. Coronaviruses: An overview of their replication and pathogenesis.Meth. Mol. Biol.201512812310.1007/978‑1‑4939‑2438‑7_1 25720466
     [Google Scholar]
  18. ChuckC.P. ChowH.F. WanD.C.C. WongK.B. Profiling of substrate specificities of 3C-like proteases from group 1, 2a, 2b, and 3 coronaviruses.PLoS One2011611e2722810.1371/journal.pone.0027228 22073294
     [Google Scholar]
  19. ChenL. GuiC. LuoX. YangQ. GüntherS. ScandellaE. DrostenC. BaiD. HeX. LudewigB. ChenJ. LuoH. YangY. YangY. ZouJ. ThielV. ChenK. ShenJ. ShenX. JiangH. Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro.J. Virol.200579117095710310.1128/JVI.79.11.7095‑7103.2005 15890949
     [Google Scholar]
  20. ZagórskaA. CzopekA. FrycM. JończykJ. Inhibitors of SARS-CoV-2 main protease (Mpro) as anti-coronavirus agents.Biomolecules202414779710.3390/biom14070797 39062511
     [Google Scholar]
  21. HuQ. XiongY. ZhuG.H. ZhangY.N. ZhangY.W. HuangP. GeG-B. The SARS‐CoV‐2 main protease (Mpro): Structure, function, and emerging therapies for COVID‐19.MedComm202233e15110.1002/mco2.151
     [Google Scholar]
  22. ArafetK. Serrano-AparicioN. LodolaA. MulhollandA.J. GonzálezF.V. ŚwiderekK. MolinerV. Mechanism of inhibition of SARS-CoV-2 M pro by N3 peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity.Chem. Sci. (Camb.)20211241433144410.1039/D0SC06195F
     [Google Scholar]
  23. YangH. XieW. XueX. YangK. MaJ. LiangW. ZhaoQ. ZhouZ. PeiD. ZiebuhrJ. HilgenfeldR. YuenK.Y. WongL. GaoG. ChenS. ChenZ. MaD. BartlamM. RaoZ. Design of wide-spectrum inhibitors targeting coronavirus main proteases.PLoS Biol.2005310e32410.1371/journal.pbio.0030324 16128623
     [Google Scholar]
  24. WangF. ChenC. TanW. YangK. YangH. Structure of main protease from human coronavirus NL63: Insights for wide spectrum anti-coronavirus drug design.Sci. Rep.2016612267710.1038/srep22677 26948040
     [Google Scholar]
  25. JinZ. DuX. XuY. DengY. LiuM. ZhaoY. ZhangB. LiX. ZhangL. PengC. DuanY. YuJ. WangL. YangK. LiuF. JiangR. YangX. YouT. LiuX. YangX. BaiF. LiuH. LiuX. GuddatL.W. XuW. XiaoG. QinC. ShiZ. JiangH. RaoZ. YangH. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors.Nature2020582781128929310.1038/s41586‑020‑2223‑y 32272481
     [Google Scholar]
  26. Guillen SchlippeY.V. HartmanM.C.T. JosephsonK. SzostakJ.W. In vitro selection of highly modified cyclic peptides that act as tight binding inhibitors.J. Am. Chem. Soc.201213425104691047710.1021/ja301017y 22428867
     [Google Scholar]
  27. VinogradovA.A. YinY. SugaH. Macrocyclic peptides as drug candidates: Recent progress and remaining challenges.J. Am. Chem. Soc.2019141104167418110.1021/jacs.8b13178 30768253
     [Google Scholar]
  28. GangD. KimD.W. ParkH.S. Cyclic peptides: Promising scaffolds for biopharmaceuticals.Genes (Basel)201891155710.3390/genes9110557 30453533
     [Google Scholar]
  29. SawyerT.K. Peptide-based drug discovery: Challenges and new therapeutics.Drug Discov.2017113410.1039/9781788011532
     [Google Scholar]
  30. MorrisonC. Constrained peptides’ time to shine?Nat. Rev. Drug Discov.201817853153310.1038/nrd.2018.125 30057410
     [Google Scholar]
  31. DoughertyP.G. SahniA. PeiD. Understanding cell penetration of cyclic peptides.Chem. Rev.201911917102411028710.1021/acs.chemrev.9b00008 31083977
     [Google Scholar]
  32. MatsoukasJ. ApostolopoulosV. LazouraE. DeraosG. MatsoukasM.T. KatsaraM. TseliosT. DeraosS. Round and round we go: Cyclic peptides in disease.Curr. Med. Chem.200613192221223210.2174/092986706777935113 16918350
     [Google Scholar]
  33. ClardyJ. WalshC. Lessons from natural molecules.Nature2004432701982983710.1038/nature03194 15602548
     [Google Scholar]
  34. QianZ. RhodesC.A. McCroskeyL.C. WenJ. Appiah-KubiG. WangD.J. GuttridgeD.C. PeiD. Enhancing the cell permeability and metabolic stability of peptidyl drugs by reversible bicyclization.Angew. Chem. Int. Ed.20175661525152910.1002/anie.201610888
     [Google Scholar]
  35. TangJ. HeY. ChenH. ShengW. WangH. Synthesis of bioactive and stabilized cyclic peptides by macrocyclization using C(sp3)-H activation.Chem. Sci. (Camb.)2017864565457010.1039/C6SC05530C
     [Google Scholar]
  36. RezaiT. YuB. MillhauserG.L. JacobsonM.P. LokeyR.S. Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers.J. Am. Chem. Soc.200612882510251110.1021/ja0563455 16492015
     [Google Scholar]
  37. QianZ. MartynaA. HardR.L. WangJ. Appiah-KubiG. CossC. PhelpsM.A. RossmanJ.S. PeiD. Discovery and mechanism of highly efficient cyclic cell-penetrating peptides.Biochemistry201655182601261210.1021/acs.biochem.6b00226 27089101
     [Google Scholar]
  38. KreutzerA.G. KrumbergerM. DiessnerE.M. ParrochaC.M.T. MorrisM.A. GuaglianoneG. ButtsC.T. NowickJ.S. A cyclic peptide inhibitor of the SARS-CoV-2 main protease.Eur. J. Med. Chem.202122111353010.1016/j.ejmech.2021.113530 34023738
     [Google Scholar]
  39. ZhangL. LinD. SunX. CurthU. DrostenC. SauerheringL. BeckerS. RoxK. HilgenfeldR. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.Science2020368648940941210.1126/science.abb3405 32198291
     [Google Scholar]
  40. MuramatsuT. TakemotoC. KimY.T. WangH. NishiiW. TeradaT. ShirouzuM. YokoyamaS. SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity.Proc. Natl. Acad. Sci. USA201611346129971300210.1073/pnas.1601327113 27799534
     [Google Scholar]
  41. ZhangL. LinD. KusovY. NianY. MaQ. WangJ. von BrunnA. LeyssenP. LankoK. NeytsJ. de WildeA. SnijderE.J. LiuH. HilgenfeldR. α-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication: Structure-based design, synthesis, and activity assessment.J. Med. Chem.20206394562457810.1021/acs.jmedchem.9b01828 32045235
     [Google Scholar]
  42. TanJ. GeorgeS. KusovY. PerbandtM. AnemüllerS. MestersJ.R. NorderH. CoutardB. LacroixC. LeyssenP. NeytsJ. HilgenfeldR. 3C protease of enterovirus 68: Structure-based design of Michael acceptor inhibitors and their broad-spectrum antiviral effects against picornaviruses.J. Virol.20138784339435110.1128/JVI.01123‑12 23388726
     [Google Scholar]
  43. DragovichP. ZhouR. SkalitzkyD.J. FuhrmanS.A. PatickA.K. FordC.E. MeadorJ.W.III WorlandS.T. Solid-phase synthesis of irreversible human rhinovirus 3C protease inhibitors. Part 1: Optimization of tripeptides incorporating N-terminal amides.Bioorg. Med. Chem.19997458959810.1016/S0968‑0896(99)00005‑X 10353638
     [Google Scholar]
  44. DaiW. ZhangB. JiangX.M. SuH. LiJ. ZhaoY. XieX. JinZ. PengJ. LiuF. LiC. LiY. BaiF. WangH. ChengX. CenX. HuS. YangX. WangJ. LiuX. XiaoG. JiangH. RaoZ. ZhangL.K. XuY. YangH. LiuH. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease.Science202036864971331133510.1126/science.abb4489 32321856
     [Google Scholar]
  45. FuL. YeF. FengY. YuF. WangQ. WuY. ZhaoC. SunH. HuangB. NiuP. SongH. ShiY. LiX. TanW. QiJ. GaoG.F. Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease.Nat. Commun.2020111441710.1038/s41467‑020‑18233‑x 32887884
     [Google Scholar]
  46. ProngayA.J. GuoZ. YaoN. PichardoJ. FischmannT. StricklandC. MyersJ.Jr WeberP.C. BeyerB.M. IngramR. HongZ. ProsiseW.W. RamanathanL. TaremiS.S. Yarosh-TomaineT. ZhangR. SeniorM. YangR.S. MalcolmB. ArasappanA. BennettF. BogenS.L. ChenK. JaoE. LiuY.T. LoveyR.G. SaksenaA.K. VenkatramanS. GirijavallabhanV. NjorogeF.G. MadisonV. Discovery of the HCV NS3/4A protease inhibitor (1R, 5S)-N-[3-Amino-1-(cyclobutyl-methyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino] carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabic-yclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization.J. Med. Chem.200750102310231810.1021/jm060173k 17444623
     [Google Scholar]
  47. KimY. LovellS. TiewK.C. MandadapuS.R. AllistonK.R. BattaileK.P. GroutasW.C. ChangK.O. Broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, noroviruses, and coronaviruses.J. Virol.20128621117541176210.1128/JVI.01348‑12 22915796
     [Google Scholar]
  48. PedersenN.C. KimY. LiuH. Galasiti KankanamalageA.C. EckstrandC. GroutasW.C. BannaschM. MeadowsJ.M. ChangK.O. Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis.J. Feline Med. Surg.201820437839210.1177/1098612X17729626 28901812
     [Google Scholar]
  49. HoffmanR.L. KaniaR.S. BrothersM.A. DaviesJ.F. FerreR.A. GajiwalaK.S. HeM. HoganR.J. KozminskiK. LiL.Y. LocknerJ.W. LouJ. MarraM.T. MitchellL.J.Jr MurrayB.W. NiemanJ.A. NoellS. PlankenS.P. RoweT. RyanK. SmithG.J.III SolowiejJ.E. SteppanC.M. TaggartB. Discovery of ketone-based covalent inhibitors of coronavirus 3CL proteases for the potential therapeutic treatment of COVID-19.J. Med. Chem.20206321127251274710.1021/acs.jmedchem.0c01063 33054210
     [Google Scholar]
  50. LiJ. LinC. ZhouX. ZhongF. ZengP. McCormickP.J. JiangH. ZhangJ. Structural basis of main proteases of coronavirus bound to drug candidate PF-07304814.J. Mol. Biol.20224341616770610.1016/j.jmb.2022.167706 35809383
     [Google Scholar]
  51. OwenD.R. AllertonC.M.N. AndersonA.S. AschenbrennerL. AveryM. BerrittS. BorasB. CardinR.D. CarloA. CoffmanK.J. DantonioA. DiL. EngH. FerreR. GajiwalaK.S. GibsonS.A. GreasleyS.E. HurstB.L. KadarE.P. KalgutkarA.S. LeeJ.C. LeeJ. LiuW. MasonS.W. NoellS. NovakJ.J. ObachR.S. OgilvieK. PatelN.C. PetterssonM. RaiD.K. ReeseM.R. SammonsM.F. SathishJ.G. SinghR.S.P. SteppanC.M. StewartA.E. TuttleJ.B. UpdykeL. VerhoestP.R. WeiL. YangQ. ZhuY. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19.Science202137465751586159310.1126/science.abl4784 34726479
     [Google Scholar]
  52. ArbelR. Wolff SagyY. HoshenM. BattatE. LavieG. SergienkoR. FrigerM. WaxmanJ.G. DaganN. BalicerR. Ben-ShlomoY. PeretzA. YaronS. SerbyD. HammermanA. NetzerD. Nirmatrelvir use and severe COVID-19 outcomes during the omicron surge.N. Engl. J. Med.2022387979079810.1056/NEJMoa2204919 36001529
     [Google Scholar]
  53. HammondJ. Leister-TebbeH. GardnerA. AbreuP. BaoW. WisemandleW. BanieckiM. HendrickV.M. DamleB. Simón-CamposA. PypstraR. RusnakJ.M. Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19.N. Engl. J. Med.2022386151397140810.1056/NEJMoa2118542 35172054
     [Google Scholar]
  54. ChakrabortyC. BhattacharyaM. AlshammariA. AlharbiM. AlbekairiT.H. ZhengC. Exploring the structural and molecular interaction landscape of nirmatrelvir and Mpro complex: The study might assist in designing more potent antivirals targeting SARS-CoV-2 and other viruses.J. Infect. Public Health202316121961197010.1016/j.jiph.2023.09.020 37883855
     [Google Scholar]
  55. WallaceA.C. LaskowskiR.A. ThorntonJ.M. LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions.Protein Eng. Des. Sel.19958212713410.1093/protein/8.2.127
     [Google Scholar]
  56. LaskowskiR.A. SwindellsM.B. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery.J. Chem. Inf. Model.201151102778278610.1021/ci200227u 21919503
     [Google Scholar]
  57. HuangC. ShuaiH. QiaoJ. HouY. ZengR. XiaA. XieL. FangZ. LiY. YoonC. HuangQ. HuB. YouJ. QuanB. ZhaoX. GuoN. ZhangS. MaR. ZhangJ. WangY. YangR. ZhangS. NanJ. XuH. WangF. LeiJ. ChuH. YangS. A new generation Mpro inhibitor with potent activity against SARS-CoV-2 omicron variants.Signal Transduct. Target. Ther.20238112810.1038/s41392‑023‑01392‑w 36928316
     [Google Scholar]
  58. de AzevedoP.H.R. CamargoP.G. ConstantL.E.C. Statine-based peptidomimetic compounds as inhibitors for SARS-CoV-2 main protease (SARS-CoV 2 Mpro).Sci. Rep.202414899110.1038/s41598‑024‑59442‑4 38637583
     [Google Scholar]
/content/journals/mroc/10.2174/0118756298349125250306033716
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Peptidomimetics as Emerging Inhibitor Against Mpro of SARS-CoV-2
Mini-Reviews in Organic Chemistry 22, 757 (2025); https://doi.org/10.2174/0118756298349125250306033716
/content/journals/mroc/10.2174/0118756298349125250306033716
/content/journals/mroc/10.2174/0118756298349125250306033716
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  • Article Type:     Review Article
Keyword(s): crystal structure; main Protease (Mpro); peptides; Peptidomimetics; receptor binding domain (RBD); SARS-CoV-2

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