Structural features in common of HBV and HIV-1 resistance against chirally-distinct nucleoside analogues entecavir and lamivudine

• Published in: Scientific reports Vol. 10; no. 1; p. 3021
• Main Authors: Yasutake, Yoshiaki, Hattori, Shin-ichiro, Tamura, Noriko, Matsuda, Kouki, Kohgo, Satoru, Maeda, Kenji, Mitsuya, Hiroaki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.02.2020; Nature Publishing Group
• Subjects: 631/326/22/1434; 631/326/596/1296; 631/326/596/1550; 631/535/1266; 82/16; 82/80; Amino acids; Antiretroviral drugs; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral drugs; Base Sequence; Chronic infection; Conformation; Crystallography, X-Ray; Deoxycytosine Nucleotides; Deoxyguanine Nucleotides; Deoxyribonucleic acid; Disease resistance; DNA; DNA, Viral - chemistry; Drug Design; Drug development; Drug resistance; Drug Resistance, Viral - drug effects; Guanine - analogs & derivatives; Guanine - chemistry; Guanine - pharmacology; Hepatitis B; Hepatitis B virus - drug effects; HIV; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus; Humanities and Social Sciences; Lamivudine; Lamivudine - chemistry; Lamivudine - pharmacology; multidisciplinary; Mutation - genetics; Nucleic Acid Conformation; Nucleoside analogs; Nucleosides - analogs & derivatives; Public health; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; RNA-directed DNA polymerase; RNA-Directed DNA Polymerase - genetics; Science; Science (multidisciplinary); Structural analysis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-59775-w

Chronic hepatitis B virus (HBV) infection is a major public health problem that affects millions of people worldwide. Nucleoside analogue reverse transcriptase (RT) inhibitors, such as entecavir (ETV) and lamivudine (3TC), serve as crucial anti-HBV drugs. However, structural studies of HBV RT have been hampered due to its unexpectedly poor solubility. Here, we show that human immunodeficiency virus type-1 (HIV-1) with HBV-associated amino acid substitutions Y115F/F116Y/Q151M in its RT (HIV Y115F/F116Y/Q151M ) is highly susceptible to ETV and 3TC. Additionally, we experimentally simulated previously reported ETV/3TC resistance for HBV using HIV Y115F/F116Y/Q151M with F160M/M184V (L180M/M204V in HBV RT) substituted. We determined crystal structures for HIV-1 RT Y115F/F116Y/Q151M :DNA complexed with 3TC-triphosphate (3TC-TP)/ETV-triphosphate (ETV-TP)/dCTP/dGTP. These structures revealed an atypically tight binding conformation of 3TC-TP, where the Met184 side-chain is pushed away by the oxathiolane of 3TC-TP and exocyclic methylene of ETV-TP. Structural analysis of RT Y115F/F116Y/Q151M/F160M/M184V :DNA:3TC-TP also demonstrated that the loosely bound 3TC-TP is misaligned at the active site to prevent a steric clash with the side chain γ-methyl of Val184. These findings shed light on the common structural mechanism of HBV and HIV-1 resistance to 3TC and ETV and should aid in the design of new agents to overcome drug resistance to 3TC and ETV.