2. Academic Validation
  3. 2'-β-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants

2'-β-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants

  • Bioorg Med Chem. 2024 Aug 1:110:117813. doi: 10.1016/j.bmc.2024.117813.
Yuki Yoshida 1,  Yushi Niimi 1,  Daichi Fushihara 1,  Hideo Katakura 1,  Ryusuke Fukui 1,  Hirotaka Murase 1,  Fumiaki Tomoike 2,  Fumitaka Hashiya 2,  Tsutomu Murakami 3,  Eiichi N Kodama 4,  Tetsuro Suzuki 5,  Kiyoshi Yasukawa 6,  Yasuaki Kimura 7,  Hiroshi Abe 8
Affiliations

Affiliations

  • 1 Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan.
  • 2 Research Center for Materials Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan.
  • 3 AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
  • 4 International Research Institute of Disaster Science, Graduate School of Medicine, and Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
  • 5 Department of Microbiology and Immunology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
  • 6 Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
  • 7 Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan. Electronic address: [email protected].
  • 8 Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan; CREST, Japan Science and Technology Agency 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan; Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan. Electronic address: [email protected].
PMID: 38954919 DOI: 10.1016/j.bmc.2024.117813
Abstract

Nucleoside Reverse Transcriptase inhibitors (NRTIs) have been extensively studied as drugs targeting HIV RT. However, the practice or use of approved NRTIs lacking the 3'-hydroxy group often promotes frequent HIV mutations and generates drug-resistance. Here, we describe a novel NRTI with 2'-β-methylselenyl modification. We found that this modification inhibited the DNA elongation reaction by HIV-1 RT despite having a 3'-hydroxy group. Moreover, the conformation of this nucleoside analog is controlled at C3'-endo, a conformation that resists excision from the elongating DNA by HIV RT. Accordingly, the designed analogs exhibited activity against both wild-type HIV and multidrug-resistant HIV mutants.

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