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Variability in the Responses of Hepatitis B Virus D-Subgenotypes to Antiviral Therapy: Designing Pan-D-Subgenotypic Reverse Transcriptase Inhibitors
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SYSNO ASEP 0553286 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Variability in the Responses of Hepatitis B Virus D-Subgenotypes to Antiviral Therapy: Designing Pan-D-Subgenotypic Reverse Transcriptase Inhibitors Author(s) Khatun, M. (IN)
Kumar, K. (IN)
Baidya, A. (IN)
Mondal, R. K. (IN)
Baszczyňski, Ondřej (UOCHB-X) RID, ORCID
Kalčic, Filip (UOCHB-X) RID, ORCID
Banerjee, S. (IN)
Dhali, G. K. (IN)
Das, K. (IN)
Chowdhury, A. (IN)
Janeba, Zlatko (UOCHB-X) RID, ORCID
Chakrabarti, S. (IN)
Datta, S. (IN)Article number e01800-21 Source Title Journal of Virology - ISSN 0022-538X
Roč. 96, č. 2 (2022)Number of pages 15 s. Language eng - English Country US - United States Keywords antiviral activity ; entecavir ; hepatitis B virus D-subgenotypes ; high throughput virtual screening ; phosphonate prodrug ; zenofovir OECD category Organic chemistry Method of publishing Limited access Institutional support UOCHB-X - RVO:61388963 UT WOS 000766836300001 EID SCOPUS 85123822001 DOI 10.1128/JVI.01800-21 Annotation Nucleos(t)ide analogues entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line monotherapies for chronic hepatitis B (CHB). Multiple HBV genotypes/subgenotypes have been described, but their impact on treatment response remains largely elusive. We investigated the effectiveness of ETV/TDF on HBV/D-subgenotypes, D1/D2/D3/D5, studied the structural/functional differences in subgenotype-specific reverse transcriptase (RT) domains of viral polymerase, and identified novel molecules with robust inhibitory activity on various D-subgenotypes. Transfection of Huh7 cells with full-length D1/D2/D3/D5 and in vitro TDF/ETV susceptibility assays demonstrated that D1/D2 had greater susceptibility to TDF/ETV while D3/D5 exhibited poorer response. Additionally, HBV load was substantially reduced in TDF-treated CHB patients carrying D1/D2 but minimally reduced in D3/D5-infected patients. Comparison of RT sequences of D-subgenotypes led to identification of unique subgenotype-specific residues, and molecular modeling/docking/simulation studies depicted differential bindings of TDF/ETV to the active site of their respective RTs. Replacement of signature residues in D3/D5 HBV clones with corresponding amino acids seen in D1/D2 improved their susceptibility to TDF/ETV. Using high throughput virtual screening, we identified N(9)-[3fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases, including N6-substituted (S)-FPMP derivative of 2,6-diaminopurine (DAP) (OB-123-VK), as potential binders of RT of different D-subgenotypes. We synthesized (S)-FPMPG prodrugs (FK-381-FEE/FK-381-SEE/FK-382) and tested their effectiveness along with OB-123-VK. Both OB-123-VK and FK-381-FEE exerted similar antiviral activities against all D-subgenotypes, although FK-381-FEE was more potent. Our study highlighted the natural variation in therapeutic response of D1/D2/D3/D5 and emphasized the need for HBV subgenotype determination before treatment. Novel molecules described here could benefit future design/discovery of pan-D-subgenotypic inhibitors. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2023 Electronic address https://doi.org/10.1128/JVI.01800-21
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