7YF6

Crystal structure of HIV-1 protease in complex with macrocyclic peptide

7YF6 の概要

• エントリーDOI: 10.2210/pdb7yf6/pdb
• 分子名称: Protease, Macrocyclic Peptide, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: viral protein-inhibitor complex, viral protein/inhibitor
• 由来する生物種: Human immunodeficiency virus 1; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 22837.33

構造登録者

Kusumoto, Y.,Sato, S.,Yamada, T.,Kozono, I.,Nakata, Z.,Asada, N.,Mitsuki, S.,Wakasa-Morimoto, C.,Tohru, M.,Watanabe, A.,Hayashi, K.,Mikamiyama, H. (登録日: 2022-07-07, 公開日: 2022-11-02, 最終更新日: 2024-11-13)

主引用文献

Kusumoto, Y.,Hayashi, K.,Sato, S.,Yamada, T.,Kozono, I.,Nakata, Z.,Asada, N.,Mitsuki, S.,Watanabe, A.,Wakasa-Morimoto, C.,Uemura, K.,Arita, S.,Miki, S.,Mizutare, T.,Mikamiyama, H.
Highly Potent and Oral Macrocyclic Peptides as a HIV-1 Protease Inhibitor: mRNA Display-Derived Hit-to-Lead Optimization.
Acs Med.Chem.Lett., 13:1634-1641, 2022

PubMed Abstract: Human immunodeficiency virus type-1 (HIV-1) protease is essential for viral propagation, and its inhibitors are key anti-HIV-1 drug candidates. In this study, we discovered a novel HIV-1 protease inhibitor (compound ) with potent antiviral activity and oral bioavailability using a structure-based drug design approach via X-ray crystal structure analysis and improved metabolic stability, starting from hit macrocyclic peptides identified by mRNA display against HIV-1 protease. We found that the improvement of the proteolytic stability of macrocyclic peptides by introducing a methyl group to the α-position of amino acid is crucial to exhibit strong antiviral activity. In addition, macrocyclic peptides, which have moderate metabolic stability and solubility in solutions containing taurocholic acid, exhibited desirable plasma total clearance and oral bioavailability. These approaches may contribute to the successful discovery and development of orally bioavailable peptide drugs.

PubMed: 36262395
DOI: 10.1021/acsmedchemlett.2c00310

実験手法

X-RAY DIFFRACTION (2.01 Å)