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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, triggering complex conformational changes that release its hold on gp41. Initially, gp41 extends to lance the target cell before ultimately collapsing into a very stable six-helix bundle or “trimer of hairpins” 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-amino acids have many potential advantages as therapeutics including insensitivity to proteases and oral bioavailability. 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 libraries of peptides for binding to HIV targets) to design and discover potent D-peptides 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, and preclinical trials are underway. Our inhibitor design also incorporates a “resistance capacitor” that provides a reserve of binding energy to combat potential resistance mutations.

HIV Vaccine Development: We are also interested in the discovery of neutralizing antibodies that target the pre-hairpin intermediate. We recently discovered that HIV has evolved a steric barrier to protect its conserved pre-hairpin fusion machinery from bulky neutralizing antibodies. We are now dissecting the sources of this steric block and using this information to design new antigens capable of inducing neutralizing antibodies that overcome this defense.

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