{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T21:28:02Z","timestamp":1769635682964,"version":"3.49.0"},"reference-count":71,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Russian Ministry of Science and Higher Education","award":["125012300658-9"],"award-info":[{"award-number":["125012300658-9"]}]},{"DOI":"10.13039\/501100006769","name":"RSF project","doi-asserted-by":"publisher","award":["25-76-30006"],"award-info":[{"award-number":["25-76-30006"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Center for Collective Use of Shemyakin\u2013Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Significant advances in coronavirus immunoprophylaxis have enabled the control of the SARS-CoV-2 pandemic. However, the continued emergence of SARS-CoV-2 variants with immune escape potential highlights the need for effective direct-acting antivirals targeting conserved viral enzymes. The SARS-CoV-2 main protease (Mpro) remains one of the most promising antiviral drug targets due to its essential role in viral replication and the high conservation of its active site across coronavirus variants. Building upon the established GC373 scaffold, we designed, synthesized, and biochemically evaluated two novel GC373-like peptidomimetic inhibitors incorporated modified glutamine-mimic residues. These analogs were designed to enhance solubility and metabolic resilience while retaining key recognition features within the Mpro active site. Both compounds demonstrated micromolar inhibitory activity in enzymatic assays, supported by molecular docking and MM-PBSA analyses consistent with stable binding. The proposed inhibitors represent viable scaffolds for further optimization of electrophilic warheads and S1\/S2 residue interactions. These findings contribute to the rational design of next-generation Mpro inhibitors and align with ongoing efforts to expand the chemical space of SARS-CoV-2 antiviral agents.<\/jats:p>","DOI":"10.3390\/cimb48020142","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T08:48:04Z","timestamp":1769590084000},"page":"142","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design and In Vitro Evaluation of Novel GC373-like SARS-CoV-2 Main Protease Inhibitors"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9805-7050","authenticated-orcid":false,"given":"Aleksandra A.","family":"Kuznetsova","sequence":"first","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8619-2415","authenticated-orcid":false,"given":"Aleksandr P.","family":"Makhin","sequence":"additional","affiliation":[{"name":"Shemyakin\u2013Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6689-4647","authenticated-orcid":false,"given":"Anatoliy A.","family":"Bulygin","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasia A.","family":"Andrianova","sequence":"additional","affiliation":[{"name":"Shemyakin\u2013Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vasily S.","family":"Miturich","sequence":"additional","affiliation":[{"name":"Shemyakin\u2013Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5065-1360","authenticated-orcid":false,"given":"Renata I.","family":"Zagitova","sequence":"additional","affiliation":[{"name":"Shemyakin\u2013Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir I.","family":"Shmygarev","sequence":"additional","affiliation":[{"name":"Shemyakin\u2013Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasia A.","family":"Fadeeva","sequence":"additional","affiliation":[{"name":"Shemyakin\u2013Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oleg N.","family":"Yatskin","sequence":"additional","affiliation":[{"name":"Shemyakin\u2013Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5603-5371","authenticated-orcid":false,"given":"Olga A.","family":"Belozerova","sequence":"additional","affiliation":[{"name":"Shemyakin\u2013Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0384-6568","authenticated-orcid":false,"given":"Ivan V.","family":"Smirnov","sequence":"additional","affiliation":[{"name":"Shemyakin\u2013Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2558-2476","authenticated-orcid":false,"given":"Ilia V.","family":"Yampolsky","sequence":"additional","affiliation":[{"name":"Shemyakin\u2013Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"Institute of Translational Medicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6336-060X","authenticated-orcid":false,"given":"Zinaida M.","family":"Kaskova","sequence":"additional","affiliation":[{"name":"Shemyakin\u2013Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"Institute of Translational Medicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4016-198X","authenticated-orcid":false,"given":"Nikita A.","family":"Kuznetsov","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"},{"name":"Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S1473-3099(20)30120-1","article-title":"An Interactive Web-Based Dashboard to Track COVID-19 in Real Time","volume":"20","author":"Dong","year":"2020","journal-title":"Lancet Infect. 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