ABSTRACT
A series of p-hydroxybenzenesulphonamides ERß receptor agonists were discovered and several compounds identified had excellent selectivity over the related ERα receptor. One of these, compound 11, had an interesting binding conformation determined by X-ray and represents an excellent starting point in the quest for further selective ERß agonists.
Subject(s)
Drug Discovery , Estrogen Receptor beta/agonists , Sulfonamides/chemistry , Sulfonamides/pharmacology , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/genetics , Estrogen Receptor beta/metabolism , Female , Humans , Ligands , Models, Chemical , Protein Binding , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/metabolismABSTRACT
Synthetic peptides that specifically bind nuclear hormone receptors offer an alternative approach to small molecules for the modulation of receptor signaling and subsequent gene expression. Here we describe the design of a series of novel stapled peptides that bind the coactivator peptide site of estrogen receptors. Using a number of biophysical techniques, including crystal structure analysis of receptor-stapled peptide complexes, we describe in detail the molecular interactions and demonstrate that all-hydrocarbon staples modulate molecular recognition events. The findings have implications for the design of stapled peptides in general.
Subject(s)
Drug Design , Peptides/chemical synthesis , Receptors, Estrogen/metabolism , Crystallography, X-Ray , Humans , Peptides/chemistry , Protein Binding , Protein Structure, Secondary , Receptors, Estrogen/chemistryABSTRACT
Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy.
