이연 (서울대학교)

한빛사논문

조회85

서울대학교

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ACS Central Sci., Aug 28 2024, 10 (8) | https://doi.org/10.1021/acscentsci.4c00548 A Novel Prodrug Strategy Based on Reversibly Degradable Guanidine Imides for High Oral Bioavailability and Prolonged Pharmacokinetics of Broad-Spectrum Anti-influenza Agents

Yujeong Jung ¹, Soo Bin Ahn ^2,3, Taeyang An ⁴, Hyeon-Min Cha ^2,3, Minjae Kim¹, Hyunjin Cheon¹, Yejin Jang², Haemi Lee ², Byungil Kim ², Meehyein Kim^2,3, Yan Lee ^1,5

¹Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.

²Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea.

³Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea.

⁴Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.

⁵School of Transdisciplinary Innovations, Seoul National University, Seoul 08826, Republic of Korea.

Y.J., S.B.A. and T.A. contributed equally to this work.

Corresponding Authors : Taeyang An, Meehyein Kim, Yan Lee

Abstract

We present orally administrable prodrugs ( OSC-GCDIs) of guanidino oseltamivir carboxylate ( GOC) based on guanidine cyclic diimide (GCDI) to treat influenza viruses. By concealing the guanidine group, which significantly limits the intestinal absorption, its prodrugs OSC-GCDIs demonstrate dramatic improvement of oral bioavailability. The most promising antiviral substance OSC-GCDI(P) readily forms covalent adducts with serum proteins via a degradable linker after the intestinal absorption. Subsequently, the active species, GOC, is released from the conjugate in a sustained manner, which greatly contributes to improving pharmacokinetic properties. Because of the remarkable improvements in both oral bioavailability and longevity of its active metabolite, OSC-GCDI(P) demonstrates outstanding therapeutic efficacy against both wild-type and oseltamivir-resistant (H275Y) influenza virus strains in a mouse infection model, even with a single oral administration.

논문정보

형식Research article
게재일2024년 08월 (BRIC 등록일 2024-09-03)
연구진국내(교신)+국외 연구진
분야 바이오·의료융합 > 바이오소재

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