Oral Presentation 8th Australasian Virology Society Meeting and 11th Annual Meeting of the Australian Centre for Hepatitis & HIV Virology Meeting 2015

New drug classes for HIV prevention: fragment-based drug discovery targeting HIV-1 reverse transcriptase     (#24)

Catherine F Latham 1 , Nicholas Barlow 2 , Joseph Bauman 3 , Adam Johnson 1 , Jennifer La 2 , Stephen Headey 2 , David Tyssen 1 , Nicolas Sluis-Cremer 4 , Eddy Arnold 3 , David Chalmers 2 , Gilda Tachedjian 1 5 6
  1. Burnet Institute, Melbourne, VIC, Australia
  2. Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
  3. CABM, Rutgers State University of New Jersey, Piscataway, NJ, USA
  4. Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, PA, USA
  5. Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia
  6. Department of Microbiology, Monash University, Clayton, VIC, Australia

HIV-1 reverse transcriptase inhibitors are currently used for treatment and now being applied to HIV prevention1, which could lead to the generation and transmission of drug resistant strains2. Our strategy to combat this dangerous overlap is to develop novel drug classes specifically for HIV prevention. We have initiated a fragment-based drug discovery (FBDD) program targeting HIV-1 RT, which is a proven drug target essential for HIV replication, and an ideal target for FBDD due to its conformational flexibility3. These “fragments”, less than half the size of conventional small molecules, can be strategically elaborated into larger, higher affinity inhibitors4, to probe for functional binding pockets to be exploited as novel target sites for drug design. Our fragment screen identified three fragment-sized compounds that inhibited the polymerase activity of both wild-type and non-nucleoside RT inhibitor (NNRTI)-resistant HIV-1 RT in the micromolar range5. Two of the three top fragment hits use mechanisms distinct from drugs available in the clinic to block HIV-1 RT.We are now testing compounds with high similarity to our top fragment compoundsto build a structure-activity relationship (SAR) profile – the first step to generating more potent RT inhibitors. We have assessed the inhibitory activity of over 150 analogs of our three fragment compounds and already identified several compounds that are ~50-200-fold more potent than the parent compounds. We have also shown using X-ray crystallography that at least one class of compounds binds to a novel allosteric site on HIV-1 RT. We are now using the SAR profile and molecular modelling to guide our medicinal chemistry program and generate high potency leads for drug development. Drug leads emerging from this work will provide a strong foundation for development of novel classes of potent antivirals for HIV prevention.

  1. Grant RM et al. (2010). N Engl J Med. 363: 2587–2599
  2. Kuritzkes DR. (2011) Curr Opin Virol. 1(6):582-9
  3. Latham CF et al (2015) Curr Top Med Chem. E-pub 1 Sept
  4. Chen et al (2012) Curr Pharm Des. 2012;18(9):1217-39.
  5. La J, Latham CF et al (2015) PNAS. 112(22):6979-84