2. Academic Validation
  3. Discovery of orally bioavailable N-acylated remdesivir derivatives with potent broad-spectrum antiviral activity

Discovery of orally bioavailable N-acylated remdesivir derivatives with potent broad-spectrum antiviral activity

  • Bioorg Chem. 2026 Jul 5:175:109758. doi: 10.1016/j.bioorg.2026.109758.
Letian Song 1,  Bing Ye 1,  Baohu Li 1,  Leentje Persoons 2,  Dirk Jochmans 3,  Johan Neyts 3,  Steven De Jonghe 4,  Shenghua Gao 5,  Peng Zhan 6,  Xinyong Liu 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, PR China.
  • 2 KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular Genetics and Therapeutics in Virology and Oncology Research Group, Herestraat 49, box 1048, 3000 Leuven, Belgium.
  • 3 KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Antiviral Drug & Vaccine Research Group, Herestraat 49, box 1043, B-3000 Leuven, Belgium.
  • 4 KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular, Structural and Translational Virology Research Group, Herestraat 49, box 1049, B-3000 Leuven, Belgium.
  • 5 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, PR China. Electronic address: [email protected].
  • 6 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, PR China. Electronic address: [email protected].
  • 7 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, PR China. Electronic address: [email protected].
PMID: 41887113 DOI: 10.1016/j.bioorg.2026.109758
Abstract

Remdesivir (RDV), a nucleoside analog targeting viral RNA-dependent RNA polymerase (RdRp), suffers from critical limitations including low oral bioavailability, plasma instability, and reliance on intravenous administration, hindering its clinical utility. To address these issues, we designed and synthesized 28 novel N-acylated derivatives by modifying the amino group on remdesivir's triazine ring. The lead compound 4f exhibited potent anti-SARS-CoV-2 activity (EC50 = 0.0862 μM) in Vero E6 cells, comparable to remdesivir (EC50 = 0.0459 μM), with reduced cytotoxicity (CC50 = 15.6 μM, SI = 181.0). Notably, 4f displayed broad-spectrum efficacy against human coronaviruses (HCoV-229E and HCoV-OC43), zika virus (ZIKV), and yellow fever virus (YFV), matching remdesivir's potency. Pharmacologically, 4f showed significantly enhanced plasma stability (half-life >8 h vs. 2 h for RDV) and reduced CYP3A4 inhibition (23.8% vs. 57.4% for RDV at 10 μM). In vivo pharmacokinetics confirmed its superior oral bioavailability (45.3% based on active metabolite GS-441524 exposure), efficiently delivering GS-441524 into systemic circulation. This N-acylation strategy overcomes key pharmacokinetic barriers of remdesivir while preserving broad-spectrum Antiviral activity, highlighting 4f as a promising oral candidate.

Keywords

Broad-spectrum; Nucleoside; Prodrug; RdRp inhibitor; SARS-CoV-2.

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