2. Academic Validation
  3. Single-Dose Oral Influenza Antiviral Prodrug Enabled by Cholesterol Conjugation

Single-Dose Oral Influenza Antiviral Prodrug Enabled by Cholesterol Conjugation

  • J Med Chem. 2025 Oct 23;68(20):21577-21586. doi: 10.1021/acs.jmedchem.5c01808.
Chenning Li 1 2,  Xun Lv 2 3,  Chenxi Cheng 1 4,  Shuihong Cheng 1,  Yiran Li 5,  Yuhai Bi 1,  Lifeng Fu 1,  George Fu Gao 1,  Xuebing Li 1 2
Affiliations

Affiliations

  • 1 Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 2 Medical School, University of Chinese Academy of Sciences, Beijing 101408, China.
  • 3 Laboratory of Microbiome and Microecological Technology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 4 College of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 117004, China.
  • 5 School of Fundamental Science and Engineering, Waseda University, Tokyo 169-8555, Japan.
PMID: 41042531 DOI: 10.1021/acs.jmedchem.5c01808
Abstract

Current influenza therapy relies heavily on oseltamivir (OSV), an ethyl ester prodrug of oseltamivir carboxylate (OC) requiring twice-daily dosing for 5 days because of its short half-life and rapid clearance. We developed a cholesterol-conjugated OC prodrug that achieved dramatically prolonged systemic OC exposure compared with OSV. The conjugate exhibited single-dose efficacy against H1N1 and H3N2 influenza in mice after oral administration under both therapeutic and prophylactic regimens, conferring up to 100% survival. Mechanistic studies revealed high plasma protein binding of conjugate (up to 89% bound) and attenuated yet sustained hydrolytic release of OC in the liver as key drivers of their prolonged retention. This long-lasting oral activity of OC-Cholesterol conjugate makes it attractive for further development to overcome the frequent dosing limitations of OSV. The Cholesterol conjugation approach should be useful for developing novel prodrugs with enhanced pharmaceutical properties.

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