Peptoids are peptidomimetic oligomers composed of N-substituted glycine units. Solid phase synthesis protocols enable strict control over the sequence of highly diverse side chain groups. Control of the primary sequence permits the design of peptoids as scaffolds for the construction of monodisperse multivalent displays that can precisely position bioactive ligands along the oligomer chain. Control of peptoid oligomer folding through macrocyclization provides stable secondary structures and permits the design of peptoids with amphiphilic features that mimic antimicrobial peptides and that perturb cellular membranes.We report studies of two families of peptoids indicating these oligomers have promising characteristics for development as �nanomedicines�. First, we describe the potent and selective antimicrobial activity of peptoids incorporating both cationic and hydrophobic side chain groups. Enforcing amphiphilic structure through macrocyclization enhances their activity against both gram positive and gram negative bacterial pathogens, including Multidrug Resistant Staphylococcus Aureus (MRSA). Second, we find that multivalent displays of the steroid ethisterone can modulate the activity of the Androgen Receptor (AR, Figure 1). Because AR activity plays a critical role in driving the development and growth of prostate cancer, the discovery of new AR antagonists is a significant goal in cancer pharmacology. Two of the peptoid-ethisterone conjugates exhibit potent anti-proliferative activity in cell culture models of late stage �castration-resistant� prostate cancer, for which new therapeutics are urgently needed. We now report in vivo evaluation of a divalent ethisterone conjugate in mouse xenografts of human prostate cancer tumors.

Biomimetic oligopeptoids: From nanostructured materials to nanomedicines

247th National Meeting (2014)

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