Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

• Published in: Scientific reports Vol. 10; no. 1; p. 10664
• Main Authors: Bulut, Haydar, Hattori, Shin-ichiro, Aoki-Ogata, Hiromi, Hayashi, Hironori, Das, Debananda, Aoki, Manabu, Davis, David A., Rao, Kalapala Venkateswara, Nyalapatla, Prasanth R., Ghosh, Arun K., Mitsuya, Hiroaki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.06.2020; Nature Publishing Group
• Subjects: 631/154; 631/535; 631/92; Adaptation; Amino acids; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Antiviral agents; Benzene; Cell Line; Cell permeability; Darunavir - pharmacology; Drug Resistance, Viral - drug effects; Fluorine; HIV; HIV Infections - drug therapy; HIV Protease - metabolism; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; Human immunodeficiency virus; Humanities and Social Sciences; Humans; multidisciplinary; Plasticity; Proteinase inhibitors; Science; Science (multidisciplinary); Sulfur; Virus Replication - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-65993-z

HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component of antiretroviral therapy. However, HIV-1 often acquires resistance to PIs. Here, seven novel PIs were synthesized, by introducing single atom changes such as an exchange of a sulfur to an oxygen, scission of a single bond in P2′-cyclopropylaminobenzothiazole (or -oxazole), and/or P1-benzene ring with fluorine scan of mono- or bis-fluorine atoms around DRV’s scaffold. X-ray structural analyses of the PIs complexed with wild-type Protease (PR WT ) and highly-multi-PI-resistance-associated PR DRV R P51 revealed that the PIs better adapt to structural plasticity in PR with resistance-associated amino acid substitutions by formation of optimal sulfur bond and adaptation of cyclopropyl ring in the S2′-subsite. Furthermore, these PIs displayed increased cell permeability and extreme anti-HIV-1 potency compared to DRV. Our work provides the basis for developing novel PIs with high potency against PI-resistant HIV-1 variants with a high genetic barrier.