10/11 - Student-Invited Lecture (chemical biology): Michael Kay, University of Utah
Michael Kay - Kay Lab website
Department of Biochemistry
University of Utah
D-peptide Inhibitors of HIV Entry
D-Peptides (composed of mirror-image D-amino acids) are promising preventative and therapeutic agents due to their insensitivity to protease degradation. Natural L-peptides are often potent and specific inhibitors, but their in vivo fragility creates delivery challenges and limits their widespread use.
The HIV envelope protein mediates viral entry via formation of a trimer-of-hairpins structure that drives viral and cellular membranes into close apposition, leading to fusion. This fusion machinery is highly conserved and provides an ideal inhibitory target, but is “undruggable” via traditional small molecule approaches.
Using mirror-image phage display and structure-assisted design, we have designed trimeric D-peptide inhibitors that block hairpin formation and inhibit viral entry with pM potency in diverse HIV strains. These inhibitors also have been engineered with a reserve of binding energy that greatly delays the emergence of resistance mutations. Cholesterol conjugation further improves potency (via membrane localization) and prolongs circulating half-life.
These D-peptides are promising candidates as both topical microbicides and systemic therapeutic agents for the prevention and treatment of HIV/AIDS. Our D-peptide design approach may also be applicable to other enveloped viruses that employ hairpin fusion mechanisms, including Ebola, RSV, and Influenza.