Research

Project 1 - Identification of a Common Allosteric Site on All GPCRs

The G-protein coupled receptors (GPCRs) represent the largest protein superfamily with more than 800 genes in human genome. GPCRs mediate cross membrane signaling and is the No. 1 drug target. In recent years, developing allosteric drugs targeting the allosteric sites on GPCRs has attracted intensive interest. A major challenge for this approach is to identify the allosteric site on GPCRs. We propose that the cavity below the transmembrane helices that partially overlaps the G-protein binding site is a common allosteric site on all GPCRs. To test this hypothesis, we're taking a multi-disciplinary approach including bioinformatics analysis, in silico screening and experimental testing.

Project 2 - Rational Design of Small Molecule Allosteric Agonists of Glucagon-Like Peptide 1 Receptor

The Glucagon-like peptide 1 receptor (GLP-1R) belongs to the pharmaceutically important Class B family of GPCRs and its incretin peptide ligand GLP-1 analogs are adopted drugs for the treatment of type -2 diabetes. Despite remarkable anti-diabetic effects, GLP-1 peptide-based drugs are limited by several disadvantages. On the other hand, developing nonpeptidic small molecule drugs targeting GLP-1R remains elusive. This project aims to design small molecule agonists that bind to the allosteric site in GLP-1R. Collaborating with Dr. Zhiyu Li at USciences and Dr. Xianxin Hua's lab at University of Pennsylvania, we've discovered small molecule ago-PAMs of GLP-1R. The success of this work will help pave the way for small molecule drug discovery targeting other Class B GPCRs through allosteric regulations.

Project 3 - Structure Optimization of Natural Product Derivatives as HIV‑1 Entry Inhibitors

Despite remarkable progresses made in the past several decades, HIV remains a major threat to human health. Combination antiretroviral therapy (cART) has been shown to reduce plasma viral loads to undetectable levels in HIV-1-infected patients. Although cART could effectively control plasma viremia, it is clear that the virus is suppressed rather than eradicated in HIV-infected individuals. In efforts to identify small molecule HIV-1 inhibitors with novel mechanisms of action, our collaborators at Duke University have identified a number of natural products that inhibits HIV-1 infection. We're utilizing computer-aided drug design tools to help with the optimization of these compounds.