We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry.
- Authors
Lai, Yen-Ting; Wang, Tao; O'Dell, Sijy; Louder, Mark K.; Schön, Arne; Cheung, Crystal S. F.; Chuang, Gwo-Yu; Druz, Aliaksandr; Lin, Bob; McKee, Krisha; Peng, Dongjun; Yang, Yongping; Zhang, Baoshan; Herschhorn, Alon; Sodroski, Joseph; Bailer, Robert T.; Doria-Rose, Nicole A.; Mascola, John R.; Langley, David R.; Kwong, Peter D.
- Abstract
Diverse 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. Temsavir, a compound that inhibits HIV entry by binding envelope (Env), is currently in clinical development. Here, Lai et al. identify a more than 10-fold improved compound and, using lattice engineering, obtain crystal structures that give insights into improved inhibition between small molecules and Env.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-07851-1