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Drug Repurposing: A Novel Approach to Discover HIV Therapies
Author(s) -
Tabassum Tasnim,
Frey Kathleen Mary
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.lb36
Subject(s) - drug repositioning , repurposing , drug , computational biology , reverse transcriptase , pharmacology , drug discovery , human immunodeficiency virus (hiv) , docking (animal) , reverse transcriptase inhibitor , etravirine , medicine , chemistry , biology , antiretroviral therapy , virology , biochemistry , viral load , ecology , rna , nursing , gene
Developing new anti‐HIV drugs is a time‐consuming and expensive process. Within a few years of approval, resistance and safety issues can limit the efficacy of new HIV therapies. Drug repurposing can serve as an efficient, cost‐effective, and low‐risk strategy for discovering new antiretrovirals. For example, this novel approach can be used to identify new HIV therapies with improved safety profiles. In this study, we hypothesize that drug repurposing can be an effective tool for discovering new therapies targeting HIV reverse transcriptase (RT). Specifically, this approach will be used to investigate the allosteric non‐nucleoside binding site (NNBP) of RT wildtype (WT). A screening library of 1508 FDA approved compounds were evaluated using molecular docking and crystal structures of RT (WT). Potential inhibitors were selected based on compound affinities ranked by docking scores and inhibitor interactions with the NNBP. Based on this analysis, 2 computational hits were selected for further investigation: alogliptin (antidiabetic) and duvelisib (kinase inhibitor). Validation using a fluorescence‐based enzymatic assay reveals that both inhibitors have IC 50 values in the micromolar range. While the screening method can be optimized, this proof of concept study shows the utility of drug repurposing for HIV RT using computational and experimental studies. Future work will focus on inhibitor screening for HIV RT variants. Support or Funding Information AACP New Investigator Award (KF)Molecular interactions of HIV reverse transcriptase (RT) in complex with alogliptin (ALG).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .