Seminarium - EFdA, a highly potent antiviral that blocks translocation of HIV Reverse Transcriptase
Seminars in Clinical Microbiology, Department of Laboratory Medicine
"EFdA, a highly potent antiviral that blocks translocation of HIV Reverse Transcriptase"
Stefan G. Sarafianos, PhD, Professor
Chancellor’s Excellence Chair in Molecular Virology, Departments of Molecular Microbiology & Immunology and Biochemistry, University of Missouri, School of Medicine
Prof Sarafianos’s lab work towards unraveling the molecular details of how biomedically-relevant enzymes function, how they are inhibited, how they develop drug resistance and towards developing drugs that will treat human disease by novel mechanisms of action. In pursuit of these goals, a combination of conventional and cutting-edge research tools, including protein biochemistry, molecular biology, fluorescence imaging/microscopy, macromolecular engineering, X-ray crystallography, molecular modeling, enzymology, and high-throughput technologies is used. Target proteins include HIV reverse transcriptase, HIV capsid protein, Hepatitis B virus (HBV) reverse transcriptase, and HBV capsid protein. Ongoing efforts focus on various steps of HIV, HBV, and Hepatitis C virus (HCV) life cycles, including cell entry, uncoating, reverse transcription, nuclear entry, assembly, and host ineractions towards developing novel therapeutics.
For more details: http://medicine.missouri.edu/mmi/?faculty=sarafianos-stefan
Prof Sarafianos presentation will focus on the novel and promising anti-HIV drug EFdA, please see a short background
Prof Sarafianos has discovered an ultrapotent mechanism of HIV inhibition by EFdA. It is by far the most potent inhibitor of HIV replication inhibiting at low picomolar concentrations by an innovative mechanism of action and very promising resistance profile.
Hypersusceptibility of tenofovir- and nonnucleoside RT inhibitor-resistant viruses: EFdA suppress NRTI-resistant viruses efficiently and is remarkably effective against the tenofovir-resistant variants. This is important because a backup drug that works well with tenofovir-resistant viruses would be very valuable.
Extraordinary in vivo activity of EFdA: i) A non-human primate study has established that EFdA has extraordinary activity in vivo. No signs of drug toxicity were observed within 6 months of continuous therapy. ii) at CROI 2016 in an oral late-breaker, the results from a dose-ranging study in macaques was presented. Baseline SHIV viral load ranged from 6 to 8 log copies/mL and following single doses viral load dropped by approximately 1.5 logs and was sustained for 7 days. PK data from a phase 1 multiple-dose study in HIV negative adults (10 mg, 30 mg and 100 mg) once-weekly for three weeks showed that with the 10 mg dose target intracellular target drug concentrations were exceeded for more than 7 days. Early data on a solid-state slow release parenteral injection formulation that has an option for removability showed sustained release for more than 180 days in rat studies, with the potential for cover to be extended to a year. A phase 1 study in six HIV positive men reported a mean viral load reduction of 1.67 log (95%CI: 1.47 to 1.87) at day 7, following a single 10 mg dose. Preclinical studies have not shown concern for mitochondrial toxicity.
Vision: In addition to the pronounced effect on tenofovir-resistant HIV strains, EFdA has the potential to change dramatically ART and PrEP – with removable slow release once-yearly dosing.