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Therapeutic agents such as small\u2010molecule drugs or peptides that interact with the Cys\u2013His present in the catalytic site of Mpro are an efficient way to inhibit the protease. Although several emergency\u2010approved vaccines showed good efficacy and drastically dropped the infection rate, evolving variants are still infecting and killing millions of people globally. While a small\u2010molecule drug (Paxlovid) received emergency approval, small\u2010molecule drugs have low target specificity and higher toxicity. Besides small\u2010molecule drugs, peptide therapeutics are thus gaining increasing popularity as they are easy to synthesize and highly selective and have limited side effects. In this study, we investigated the therapeutic value of 67 peptides targeting Mpro using molecular docking. Subsequently, molecular dynamics (MD) simulations were implemented on eight protein\u2013peptide complexes to obtain molecular\u2010level information on the interaction between these peptides and the Mpro active site, which revealed that temporin L, indolicidin, and lymphocytic choriomeningitis virus (LCMV) GP1 are the best candidates in terms of stability, interaction, and structural compactness. These peptides were synthesized using the solid\u2010phase peptide synthesis protocol, purified by reversed\u2010phase high\u2010performance liquid chromatography (RP\u2010HPLC), and authenticated by mass spectrometry (MS). The in vitro fluorometric Mpro activity assay was used to validate the computational results, where temporin L and indolicidin were observed to be very active against SARS\u2010CoV\u20102 Mpro with IC<jats:sub>50<\/jats:sub> values of 38.80 and 87.23\u2009\u03bcM, respectively. A liquid chromatography\u2013MS (LC\u2013MS) assay was developed, and the IC<jats:sub>50<\/jats:sub> value of temporin L was measured at 23.8\u2009\u03bcM. The solution\u2010state nuclear magnetic resonance (NMR) structure of temporin L was determined in the absence of sodium dodecyl sulfate (SDS) micelles and was compared to previous temporin structures. This combined investigation provides critical insights and assists us to further develop peptide inhibitors of SARS\u2010CoV\u20102 Mpro through structural guided investigation.<\/jats:p>","DOI":"10.1002\/psc.3553","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T07:19:50Z","timestamp":1701328790000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Antiviral peptides inhibiting the main protease of SARS\u2010CoV\u20102 investigated by computational screening and in vitro protease assay"],"prefix":"10.1002","volume":"30","author":[{"given":"James","family":"Stewart","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry Kennesaw State University  Kennesaw GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakaria","family":"Shawon","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute University of Utah  Salt Lake City UT USA"},{"name":"Division of Infectious Diseases and Division of Computer\u2010Aided Drug Design The Red\u2010Green Research Centre, BICCB, Tejgaon  Dhaka Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8235-3517","authenticated-orcid":false,"given":"Md Ackas","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Kennesaw State University  Kennesaw GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blaise","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Kennesaw State University  Kennesaw GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. 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