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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Lai YT,Wang T,O'Dell S,Louder MK,Schön A,Cheung CSF,Chuang GY,Druz A,Lin B,McKee K,Peng D,Yang Y,Zhang B,Herschhorn A,Sodroski J,Bailer RT,Doria-Rose NA,Mascola JR,Langley DR,Kwong PDdoi
10.1038/s41467-018-07851-1subject
Has Abstractpub_date
2019-01-03 00:00:00pages
47issue
1issn
2041-1723pii
10.1038/s41467-018-07851-1journal_volume
10pub_type
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