{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:45:48Z","timestamp":1789073148671,"version":"build-2803163510"},"reference-count":112,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T00:00:00Z","timestamp":1768608000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2025A1515010495"],"award-info":[{"award-number":["2025A1515010495"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Youth Innovative Talents Project from the Department of Education of Guangdong Province","award":["2024KQNCX197"],"award-info":[{"award-number":["2024KQNCX197"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The continuous emergence of SARS-CoV-2 variants, especially the Omicron strain with its heightened transmissibility, has posed ongoing challenges to the efficacy of existing vaccine and drug regimens. This situation highlights the pressing demand for antiviral drugs employing novel mechanisms of action. Pentacyclic triterpenoids (PTs), a structurally varied group of compounds derived from plants, exhibit both antiviral and anti-inflammatory activities, making them attractive candidates for further therapeutic development. These natural products, along with their saponin derivatives, show broad-spectrum inhibitory effects against multiple SARS-CoV-2 variants (from Alpha to Omicron) via interactions with multiple targets, such as the spike protein, main protease (Mpro), RNA-dependent RNA polymerase (RdRp), and inflammatory signaling pathways. This review consolidates recent findings on PTs and their saponins, emphasizing their influence on the key structural features required for inhibiting viral attachment, membrane fusion, reverse transcription, and protease function. We systematically summarized the structure\u2013activity relationships and their antiviral results of PTs based on different target proteins in existing studies. Furthermore, this work points toward new strategies for designing multi-target PT-based inhibitors with improved efficacy against Omicron and future variants.<\/jats:p>","DOI":"10.3390\/molecules31020325","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T09:57:02Z","timestamp":1768816622000},"page":"325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Emerging Promise of Pentacyclic Triterpenoid Derivatives as Novel Antiviral Agents Against SARS-CoV-2 Variants"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7715-8872","authenticated-orcid":false,"given":"Xin","family":"Wan","sequence":"first","affiliation":[{"name":"School of Pharmacy and Laboratory Medicine, Huizhou Health Sciences Polytechnic, Huizhou 516000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxuan","family":"Cui","sequence":"additional","affiliation":[{"name":"Key Laboratory for Biobased Materials and Energy, Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Laboratory Medicine, Huizhou Health Sciences Polytechnic, Huizhou 516000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junran","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory for Biobased Materials and Energy, Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangan","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory for Biobased Materials and Energy, Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Laboratory Medicine, Huizhou Health Sciences Polytechnic, Huizhou 516000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaopeng","family":"Song","sequence":"additional","affiliation":[{"name":"Key Laboratory for Biobased Materials and Energy, Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1146\/annurev-micro-020518-115759","article-title":"Human Coronavirus: Host-Pathogen Interaction","volume":"73","author":"Fung","year":"2019","journal-title":"Annu. 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