Poster Presentation The 44th Lorne Conference on Protein Structure and Function 2019

Parallel solid phase synthesis: an efficient strategy for the fragment based drug design of novel HIV-1 reverse transcriptase inhibitors (#154)

Shane L Dawson 1 , Jo-anne Pinson 1 , Nicholas Barlow 1 , Adam Johnson 2 , George Mbogo 2 , Catherine F Latham 2 , Steven Headey 1 , Menachem Gunzburg 1 , Nicolas Sluis-Cremer 3 , Eddy Arnold 4 , Philip Thompson 1 , Gilda Tachedjian 2 , David Chalmers 1
  1. Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia
  2. Burnet Institute, Melbourne, Victoria, Australia
  3. Department of Infectious Diseases, University of Pittsburgh, Pittsburgh, PA, USA
  4. Rutgers State University of New Jersey, Piscataway, New Jersey, USA

HIV-1 reverse transcriptase (RT) inhibitors are a major component in antiretroviral therapy (ART) for successfully controlling the viral load in patients with HIV. However, the continual development of drug resistant HIV strains, long term ART toxicity or patient intolerance limits the effectiveness of existing treatment and prevention programs. Current HIV antiretroviral drugs in the discovery pipeline focus on already established drug classes which, due to the lack of diversity, can result in limited treatment options and susceptibility of cross-resistance to entire drug classes[1]. This demonstrates the need for novel HIV antiretroviral drugs. Fragment-based Drug Design (FBDD) is an established approach in both academic and industrial drug discovery sectors[2]. We have exploited this approach to elaborate on previously identified fragments targeting novel binding pockets of HIV-RT[3]. Consistent with all fragment efforts, there is a requirement to synthesise a large number of compounds for improvements in potency, and purification of individual compounds is often a time-consuming process. We present an optimized parallel solid phase (SP) approach as a more efficient means for the synthesis of small molecule libraries. This SP approach removes the need for more traditional reaction purification schemes which are often significantly lengthier, and require the purification of intermediates which is often required after each step of the synthetic pathway. We used a combination of RT activity inhibition assays and Surface Plasmon Resonance assays to evaluate each compound for RT inhibition and binding. Our assays used wild-type and non-nucleoside RT inhibitor (NNRTI)-resistant HIV-1 RT mutants to ensure the libraries were binding at sites distinct from existing NNRTI drugs. We demonstrate the practical application of SP as a means to improve efficiency in early stage fragment development for novel HIV antiretroviral drugs.  

  1. Abdul, A.W. and T. Gilda, Why Do We Need New Drug Classes for HIV Treatment and Prevention? Current Topics in Medicinal Chemistry, 2016. 16(12): p. 1343-1349.
  2. Erlanson, D.A., et al., Twenty years on: the impact of fragments on drug discovery. Nature Reviews Drug Discovery, 2016. 15: p. 605.
  3. La, J., et al., Identification of mechanistically distinct inhibitors of HIV-1 reverse transcriptase through fragment screening. Proceedings of the National Academy of Sciences, 2015. 112(22): p. 6979-6984.