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Michael S. Kay

Associate Professor of Biochemistry

B.A. Cornell University

M.D./Ph.D. Stanford University

Research

References

kay@biochem.utah.edu

Michael Kay's Lab Page

Michael Kay's PubMed Literature Search

Research

We study the mechanism of viral entry in HIV. HIV has obvious medical importance as the causative agent of AIDS, and our research focuses on applying our improving knowledge of the HIV entry mechanism towards the development of novel HIV entry inhibitors.

Understanding and Inhibiting HIV Entry: HIV entry is mediated by the HIV envelope protein (gp41/gp120 complex). Initially, gp41 is trapped in a metastable conformation by its interaction with gp120. Fusion of the viral and cellular membranes is initiated when gp120 contacts CD4 and a chemokine co-receptor on a target cell. This interaction triggers complex conformational changes that propagate to gp41 and allow it to harpoon the target cell. gp41 ultimately collapses into a very stable "trimer of hairpins" structure that pulls the viral and target membranes together, leading to fusion (see figure). During this conformational transition, gp41 forms a transient pre-hairpin intermediate containing a trimeric coiled coil (N-trimer region). This region is highly conserved and a very promising inhibitory target. A major focus of our lab is the development of peptide and protein inhibitors that bind to this pre-hairpin intermediate and prevent HIV entry.

D-peptide Inhibitors of HIV Entry: In one approach, we are developing small D-amino acid peptides (D-peptides) that target the pre-hairpin intermediate. D-peptides are insensitive to proteases and have the potential to last in the body much longer than natural L-peptides. These peptides also allow us to study for the first time the nature of high affinity interactions between L and D-peptides. We combine high-resolution structural data (in collaboration with Chris Hill's lab) and phage display (panning highly diverse peptide libraries for binding to HIV targets) to design and discover potent D-peptide entry inhibitors. We currently have several promising D-peptide entry inhibitors with sub-nM potency that are undergoing preclinical trials for the prevention and treatment of HIV/AIDS (see figure for a model of a trimeric D-peptide inhibitor binding to the pre-hairpin intermediate). The durability of D-peptides is particularly suitable for use as a microbicide, a topical preventative agent. Our inhibitor design also incorporates a unique "resistance capacitor" that provides a reserve of binding energy to combat potential resistance mutations (a major problem with HIV drugs).

D-peptide Inhibitors for Other Viruses: We are extending our success in designing HIV entry inhibitors to target other viruses that use a similar hairpin fusion mechanism. This mechanism is used by many viruses of medical interest including Ebola, Influenza, RSV, West Nile Virus, and Dengue.

Mechanical Properties of HIV: After a new virion buds from the cell, it undergoes a "maturation" process induced by the action of HIV protease that is required for infectivity. Maturation is accompanied by dramatic morphological changes in the viral particle, as seen by EM. We recently reported the discovery of a dramatic "stiffness switch" during maturation that reduces particle stiffness by ~14-fold. We are now studying the mechanism and functional role of this switch.

References