An ultralong-acting tenofovir ProTide nanoformulation achieves monthslong HBV suppression

Srijanee Das, Weimin Wang, Murali Ganesan, Franchesca Fonseca-Lanza, Denise A. Cobb, Grace Bybee, Yimin Sun, Lili Guo, Brandon Hanson, Samuel M. Cohen, Howard E. Gendelman, Natalia A. Osna, Benson J. Edagwa, Larisa Y. Poluektova

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Treatment of chronic hepatitis B virus (HBV) requires lifelong daily therapy. However, suboptimal adherence to the existing daily therapy has led to the need for ultralong-acting antivirals. A lipophilic and hydrophobic ProTide was made by replacing the alanyl isopropyl ester present in tenofovir alafenamide (TAF) with a docosyl phenyl alanyl ester, now referred to as M1TFV. NM1TFV and nanoformulated TAF (NTAF) nanocrystals were formulated by high-pressure homogenization. A single intramuscular injection of NM1TFV, but not NTAF, delivered at a dose of TFV equivalents (168 milligrams per kilogram) demonstrated monthslong antiviral activities in both HBV-transgenic and human hepatocyte transplanted TK-NOG mice. The suppression of HBV DNA in blood was maintained for 3 months. Laboratory experiments on HBV-transfected HepG2.2.15 cells affirmed the animal results and the critical role of docosanol in the sustained NM1TFV antiviral responses. These results provide clear “proof of concept” toward an emerging therapeutic paradigm for the treatment and prevention of HBV infection.

Original languageEnglish (US)
Article numbereade9582
JournalScience Advances
Volume8
Issue number51
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • General

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