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The research in my laboratory focuses on both understanding the
chemical basis of molecular recognition in protein-protein and protein-ligand
complexes and translating such basic knowledge into the discovery of new
drugs. By integrating the tools of structure-based drug design, synthetic
chemistry, biophysical and biochemical analysis, and molecular and
cellular biology, our primary interest is to generate novel chemical
modulators of protein biological function and use them as small
molecular probes to explore the structure-function relationship and
molecular mechanism of biological processes involved in immunology and cell biology.
The second goal of our research is to further develop these molecular
probes into new therapeutic agents for the treatment of human disease.
This is illustrated by several examples of our recent research as outlined
below.
 CD4 Protein in Immune Response. We are interested in the design
of small molecule inhibitors of CD4 as molecular probes to study the role
of CD4 in T-cell function and potential therapeutic agents to treat or
prevent CD4-mediated autoimmune disease and transplant rejection. We have
combined molecular design and peptide chemistry techniques to synthesize
CD4 peptide analogs possessing significant immunoregulatory activity in
vitro and in vivo. In parallel to synthetic peptide chemistry,
we have applied another approach of computer screening to discover non-peptidic
organic inhibitors. These CD4 inhibitors are useful tools to investigate
the mechanism of CD4 self-association and interaction with other proteins
on T-cell surface. Together with collaborators in medicine, we have
advanced one of these inhibitors into a human clinical trial for
preventing graft-versus-host disease in bone marrow transplant patients.
Chemokine Receptors in HIV Entry. Chemokine receptors such as
CXCR4 and CCR5 are coreceptors required for the cellular entry of human
immunodeficiency virus (HIV). We are interested in understanding how these
receptors recognize HIV as well as their natural and synthetic ligands.
Such information will help us to design novel inhibitors to block the
viral entry process of HIV. We have studied a chemokine vMIP-II that can
bind both CXCR4 and CCR5 and block infection by different HIV strains. We
have found that synthetic peptides derived from vMIP-II N-terminus
selectively bind CXCR4 and inhibit the entry and replication of HIV via
this receptor. In addition to our strong interest in bringing such agents
to the clinic, we use these synthetic peptides as chemical probes to study
chemokine receptor function and signaling. For example, recently we have
analyzed the CXCR4 binding of peptide analogs composed of all D-amino
acids and obtained surprising new insights into the stereospecificity of
the receptor-ligand interface.
Bcl-2 Family Proteins in Apoptosis. Bcl-2 family proteins are
key regulators of apoptosis or programmed cell death which is implicated
in many human diseases including cancer and neurodegenerative disorder. We
have shown that synthetic cell permeable Bcl-2 binding peptides can induce
apoptosis of tumor cells and suppress the growth of tumor in mice. In
addition, we have discovered using computer screening technique organic
compounds that mimic the tumor-killing effect of Bcl-2 binding peptides.
These findings have demonstrated a novel approach of using chemical
modulation of Bcl-2 function as an anti-cancer strategy. We are planning
further studies in order to advance these Bcl-2 inhibitors to clinical
trials in humans as a new class of anti-cancer drugs. In addition, the way
in which Bcl-2 family members control apoptosis remains unclear and
controversial. Bcl-2 ligands discovered here are valuable tools to study
these important mechanistic questions.
Overall Approach
BCl-2 in Apoptosis
CD4 in Immune Response
CD4-gp120 in HIV
CD8 in Immune Response
IgE in Allergy
Chemokine Receptors in HIV
De-novo Protein Design
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