7-Deaza-7-fluoro modification confers on 4′-cyano-nucleosides potent activity against entecavir/adefovir-resistant HBV variants and favorable safety

Publication date: Available online 18 February 2020Source: Antiviral ResearchAuthor(s): Sanae Hayashi, Nobuyo Higashi-Kuwata, Debananda Das, Kota Tomaya, Kohei Yamada, Shuko Murakami, David J. Venzon, Shin-ichiro Hattori, Masanori Isogawa, Stefan G. Sarafianos, Hiroaki Mitsuya, Yasuhito TanakaAbstractWe designed, synthesized and identified a novel nucleoside derivative, 4′-C-cyano-7-deaza-7-fluoro-2′-deoxyadenosine (CdFA), which exerts potent anti-HBV activity (IC50 ∼26 nM) with favorable hepatocytotoxicity (CC50 ∼56 μM). Southern blot analysis using wild-type HBV (HBVWT)-encoding-plasmid-transfected HepG2 cells revealed that CdFA efficiently suppresses the production of HBVWT (IC50 = 153.7 nM), entecavir (ETV)-resistant HBV carrying L180M/S202G/M204V substitutions (HBVETVR; IC50 = 373.2 nM), and adefovir dipivoxil (ADV)-resistant HBV carrying A181T/N236T substitutions (HBVADVR; IC50=192.6 nM), whereas ETV and ADV were less potent against HBVETVR and HBVADVR (IC50:>1,000 and 4,022.5 nM, respectively). Once-daily peroral administration of CdFA to human-liver-chimeric mice over 14 days (1 mg/kg/day) comparably blocked HBVWT and HBVETVR viremia by 0.7 and 1.2 logs, respectively, without significant changes in body-weight or serum human-albumin levels, although ETV only slightly suppressed HBVETVR viremia (CdFA vs ETV; p = 0.032). Molecular modeling suggested that ETV-TP has good nonpolar interactions with HBVWT reverse transcriptase (RTWT)'s Me...
Source: Antiviral Therapy - Category: Virology Source Type: research