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Michael S. Kay

Assistant Professor of Biochemistry

B.A. Cornell University

M.D./Ph.D. Stanford University

Research

References

kay@biochem.utah.edu

Michael Kay's Lab Page

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 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 the HIV entry.

In one approach, we are developing small D-amino acid peptides (D-peptides) that inhibit HIV membrane fusion and entry. D-amino acids have many potential advantages as therapeutics including low immunogenicity, protease resistance, 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 employ semi-rational design that combines high-resolution structural data (obtained in collaboration with Chris Hill's lab) and phage display selections (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 (see Figure 2) and are working to improve their potency with the goal of future clinical use.

We are also interested in HIV vaccine development, particularly the discovery of neutralizing antibodies that target the pre-hairpin intermediate. We have recently discovered that HIV has evolved a steric barrier to protect its conserved pre-hairpin fusion machinery from bulky neutralizing antibodies. We are dissecting the sources of this steric defense and developing strategies to overcome it.

Finally, we are studying the gp41-gp120 interaction to understand how CD4 and coreceptor binding lead to the conformational changes necessary for membrane fusion. Unfortunately, the gp41/gp120 interface has resisted high-resolution structural efforts, largely due to the metastability of gp41 (making it difficult to maintain gp41 in its pre-fusion state). We are taking a protein design approach to mimic this interface. These studies will also aid efforts to design inhibitors that disrupt the gp41/gp120 interface.

References