2′-β-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants

Yuki Yoshida; Yushi Niimi; Daichi Fushihara; Hideo Katakura; Ryusuke Fukui; Hirotaka Murase; Fumiaki Tomoike; Fumitaka Hashiya; Tsutomu Murakami; Eiichi N. Kodama; Tetsuro Suzuki; Kiyoshi Yasukawa; Yasuaki Kimura; Hiroshi Abe

doi:10.1016/j.bmc.2024.117813

2′-β-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants

Yuki Yoshida, Yushi Niimi, Daichi Fushihara, Hideo Katakura, Ryusuke Fukui, Hirotaka Murase, Fumiaki Tomoike, Fumitaka Hashiya, Tsutomu Murakami, Eiichi N. Kodama, Tetsuro Suzuki, Kiyoshi Yasukawa, Yasuaki Kimura, Hiroshi Abe

IRIDeS - Disaster Medical Science Division

Research output: Contribution to journal › Article › peer-review

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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 3ʹ-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.

Original language	English
Article number	117813
Journal	Bioorganic and Medicinal Chemistry
Volume	110
DOIs	https://doi.org/10.1016/j.bmc.2024.117813
Publication status	Published - 2024 Aug 1

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Yoshida, Y., Niimi, Y., Fushihara, D., Katakura, H., Fukui, R., Murase, H., Tomoike, F., Hashiya, F., Murakami, T., Kodama, E. N., Suzuki, T., Yasukawa, K., Kimura, Y., & Abe, H. (2024). 2′-β-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants. Bioorganic and Medicinal Chemistry, 110, Article 117813. https://doi.org/10.1016/j.bmc.2024.117813

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title = "2′-β-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants",

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 3ʹ-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.",

author = "Yuki Yoshida and Yushi Niimi and Daichi Fushihara and Hideo Katakura and Ryusuke Fukui and Hirotaka Murase and Fumiaki Tomoike and Fumitaka Hashiya and Tsutomu Murakami and Kodama, {Eiichi N.} and Tetsuro Suzuki and Kiyoshi Yasukawa and Yasuaki Kimura and Hiroshi Abe",

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doi = "10.1016/j.bmc.2024.117813",

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Yoshida, Y, Niimi, Y, Fushihara, D, Katakura, H, Fukui, R, Murase, H, Tomoike, F, Hashiya, F, Murakami, T, Kodama, EN, Suzuki, T, Yasukawa, K, Kimura, Y & Abe, H 2024, '2′-β-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants', Bioorganic and Medicinal Chemistry, vol. 110, 117813. https://doi.org/10.1016/j.bmc.2024.117813

TY - JOUR

T1 - 2′-β-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants

AU - Yoshida, Yuki

AU - Niimi, Yushi

AU - Fushihara, Daichi

AU - Katakura, Hideo

AU - Fukui, Ryusuke

AU - Murase, Hirotaka

AU - Tomoike, Fumiaki

AU - Hashiya, Fumitaka

AU - Murakami, Tsutomu

AU - Kodama, Eiichi N.

AU - Suzuki, Tetsuro

AU - Yasukawa, Kiyoshi

AU - Kimura, Yasuaki

AU - Abe, Hiroshi

PY - 2024/8/1

Y1 - 2024/8/1

N2 - Nucleoside reverse transcriptase inhibitors (NRTIs) have been extensively studied as drugs targeting HIV RT. However, the practice or use of approved NRTIs lacking the 3ʹ-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.

AB - Nucleoside reverse transcriptase inhibitors (NRTIs) have been extensively studied as drugs targeting HIV RT. However, the practice or use of approved NRTIs lacking the 3ʹ-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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VL - 110

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

M1 - 117813

ER -

2′-β-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants

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