Natural Product Derived CXCR4/CCR2 Dual-targeted Fusion Inhibitors

The chemokine receptors CCR5 and CXCR4 have been shown to act as co-receptors that are required for cellular entry by the human immunodeficiency virus (HIV-1). There has been success with CCR5 antagonists being used as HIV fusion inhibitors, while CXCR4 antagonists have failed due to side effects and inefficacy. However, there are no such reports for the CXCR4/CCR2 dual-targeting fusion inhibitors. These two receptors co-exist as a hetero-oligomeric complex at the surface of T cells and monocytes. Because the antagonisms of CCR2 lead to the cross-inhibition of other receptors, we expect that the dual-receptor targeted antagonists would lead to the effective inhibition of HIV fusion regulated by the CXCR4 co-receptor. In this project, we will employ modern docking approaches in combination with novel statistical scoring functions developed in our laboratory for structure-based virtual screening (VS). The newly solved crystal structures of the human CXCR4 chemokine receptor will be utilized to dock against the unique collection of Natural Products chemical libraries developed in the State Key Laboratory of Natural and Biomimetic Drugs in Peking University of China. We will also build the structural models of the CCR2 receptor as well as other CXC chemokine receptors (CXCR1-CXCR7) and CC chemokine receptors (CCR1-CCR11) for cross-docking and subtype selectivity studies. The putative hits identified will be submitted to the NIMH Psychactive Drug Screening Program (PDSP) and the Virology Core Laboratory of DC D-CFAR for in vitro binding and antiviral activities evaluation. The confirmed hits will be sent to Prof. L. Zhang's laboratory in China for further hit-to-lead and lead optimization thus translate toward the Investigational New Drug (IND) application.