Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry
Copyright policy )Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry
AbstractDiverse entry inhibitors targeting the gp120 subunit of the HIV-1 envelope (Env) trimer have been developed including BMS-626529, also called temsavir, a prodrug version of which is currently in phase III clinical trials. Here we report the characterization of a panel of small-molecule inhibitors including BMS-818251, which we show to be >10-fold more potent than temsavir on a cross-clade panel of 208-HIV-1 strains, as well as the engineering of a crystal lattice to enable structure determination of the interaction between these inhibitors and the HIV-1 Env trimer at higher resolution. By altering crystallization lattice chaperones, we identify a lattice with both improved diffraction and robust co-crystallization of HIV-1 Env trimers from different clades complexed to entry inhibitors with a range of binding affinities. The improved diffraction reveals BMS-818251 to utilize functional groups that interact with gp120 residues from the conserved β20-β21 hairpin to improve potency.
- Johns Hopkins University United States
- University of Minnesota System United States
- Bristol-Myers Squibb (Germany) Germany
- Harvard University United States
- University of Minnesota Morris United States
Protein Conformation, Science, Q, Chemical Engineering, HIV Envelope Protein gp120, Triazoles, Virus Internalization, Crystallography, X-Ray, Article, Piperazines, Molecular Docking Simulation, HIV Fusion Inhibitors, Drug Design, HIV-1, Humans, Nanoparticles, Protein Multimerization, HeLa Cells, Protein Binding
Protein Conformation, Science, Q, Chemical Engineering, HIV Envelope Protein gp120, Triazoles, Virus Internalization, Crystallography, X-Ray, Article, Piperazines, Molecular Docking Simulation, HIV Fusion Inhibitors, Drug Design, HIV-1, Humans, Nanoparticles, Protein Multimerization, HeLa Cells, Protein Binding
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