Ziwei Huang, PhD

Current Appointments

• Professor and Chair of Pharmacology

Hospital Campus

• Downtown

Education & Fellowships

• Postdoctoral Fellow: University of California at San Francisco, 1994
• PhD: University of California at San Diego, 1993, Chemistry

Publications

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Research Abstract

My laboratory works on the broad area of molecular, cellular and chemical pharmacology with specific interests in developing and applying computer-aided, structure-based techniques to study protein-protein and receptor-ligand interactions implicated in cancer, viral infection, immune and inflammatory disease, neurodegeneration, cardiovascular disease, and stem cell-based regenerative medicine.  The overall focus is on both fundamental basic research to study and understand the pharmacological mechanism of protein-protein or receptor-ligand/inhibitor interactions and translational drug discovery research to apply such studies of biological recognition to the development of new therapeutics for treating human diseases.  Currently we are conducting a number of research projects as highlighted below.

We are studying the structure-function relationship and mechanism in biological recognition and signal transduction of chemokine receptors and their ligands.  For example, we study CXCR4 and CCR5, two principal coreceptors of HIV entry, to understand their role in HIV entry mechanism and gain more general understanding of the signaling mechanism of G protein-coupled receptors (GPCRs).  We have applied a combination of chemistry, biophysics, pharmacology, and cell biology to study the structure and interaction of these GPCRs and designed novel synthetic inhibitors targeting HIV infection via these GPCR coreceptors.  In addition to HIV, we are interested in other infectious diseases such as hepatitis C virus (HCV) and west nile virus (WNV) and developing new inhibitors of the infection by these viruses.

We are interested in the study of proteins involved in apoptosis and angiogenesis of cancer.  For example, Bcl-2 family and IAP family of proteins are involved in apoptosis of cancer cells.  We are studying the structure-function relationship of these proteins and developing new small molecules targeted to these proteins capable of triggering apoptosis of cancer cells.  The Eph receptor family proteins are involved in angiogenesis of cancer.  We are investigating the pharmacology and biochemistry of Eph ligand-receptor interactions and developing new synthetic molecules (both modified peptides and non-peptidic small molecules) to probe and regulate Eph receptor functions in cancer.

Finally, we have initiated new research in the area of stem cell-based therapeutic discovery.  For example, by targeting the SDF-1a/CXCR4 axis which is a master regulator of both normal stem cell trafficking and cancer stem cell metastasis, we are working on the discovery of novel agents that can specifically direct/promote the migration of neural stem cells toward the injury sites in the brain for regenerative medicine or blocking the metastasis of cancer stem cells for the treatment of cancer.

The central theme for all of our research projects, some highlighted above, is the understanding of the pharmacological basis of protein-protein and protein-ligand interactions and translation of such basic knowledge into the discovery of new drugs.  As detailed in many of our publications, our laboratory has developed and applied various techniques related to drug discovery, such as computational chemistry and structure-based drug design, synthetic chemistry, biophysical and biochemical analysis, and molecular and cellular biology and pharmacology.

Selected References

1. Wang JL, Liu D, Zhang ZJ, Shan S, Han X, Srinivasula SM, Croce CM, Alnemri ES and Huang Z.  Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells.  Proc. Natl. Acad. Sci. USA, 97: 7124-7129, 2000.
2. Wang JL, Zhang ZJ, Choksi S, Shan S, Lu Z, Croce CM, Alnemri ES, Korngold R and Huang Z.  Cell permeable Bcl-2 binding peptides: a chemical approach to apoptosis induction in tumor cells.  Cancer Res., 60: 1498-1502, 2000.
3. Zhou N, Luo Z, Luo J, Liu D, Hall JW, Pomerantz RJ and Huang Z. Structural and functional characterization of human CXCR4 as a chemokine receptor and HIV-1 co-receptor by mutagenesis and molecular modeling studies.  J. Biol. Chem., 276: 42826-42833, 2001.
4. Zhou N, Luo Z, Luo J, Fan X, Cayabyab M, Hiraoka M, Liu D, Han X, Pesavento J, Dong C, Wang Y, An J, Kaji H, Sodroski JG and Huang Z.  Exploring the stereochemistry of CXCR4-peptide recognition and inhibiting HIV-1 entry with D-peptides derived from chemokines.  J. Biol. Chem., 277: 17476-17485, 2002.
5. An J, Chen Y and Huang Z. Critical upstream signals of cytochrome c release induced by a novel Bcl-2 inhibitor.  J. Biol. Chem., 279:19133-40, 2004.
6. Yang B, Liu D and Huang Z. Synthesis and helical structure of lactam bridged BH3 peptides derived from pro-apoptotic Bcl-2 family proteins. Bioorg. Med. Chem. Lett.,14:1403-1406, 2004.
7. Tian S, Choi WT, Liu D, Pasavento J, Wang Y, An J, Sodroski JG and Huang Z.  Distinct functional sites for human immunodeficiency virus type 1 and stromal cell-derived factor 1a on CXCR4 transmembrane helical domains.  Journal of Virology, 2005, 79: 12667-12673.
8. Dong, CZ, Kumar S, Choi WT, Madani N, Tian S, An J, Sodroski JG and Huang Z.   Different stereochemical requirements for CXCR4 binding and signaling functions as revealed by an anti-HIV, D-amino acid-containing SMM-chemokine ligand.  J. Med. Chem., 2005, 48: 7923-2924.
9. Choi WT, Tian S, Dong CZ, Kumar S, Liu D, Madani N, An J, Sodroski JG and Huang Z.  Unique ligand binding sites on CXCR4 probed by a chemical biology approach: implications for the design of selective human immunodeficiency virus type 1 inhibitors.  Journal of Virology, 2005, 79: 15398-15404.
10. Kumar S, Choi WT, Dong CZ, Madani N, Tian S, Liu D, Wang Y, Pesavento J, Wang J, Fan X, Yuan J, An J, Sodroski JG, Richman DD and Huang Z.  SMM-Chemokines: a class of unnatural Synthetic molecules as chemical probes of chemokine receptor biology and leads for therapeutic development.  Chemistry & Biology, 2006, 13: 1-11.
11. Nie A, Wang J and Huang Z. Microwave-assisted Solution Parallel Synthesis of 2,4,6-trisubstituted Pyrimidines. J. Comb.  Chem., 2006, 8:646-8.
12. An J, Chervin AS, Nie A, Ducoff HS, and Huang Z.  Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor.  Oncogene, 2007, 26: 652-661.
13. Li Y, Guo Y, Kumar S, Liu D and Huang Z. Crystal structure of a chemically synthesized, anti-HIV chemokine vMIP-II.  PROTEINS: Structure, Function, and Bioinformatics, 2007, 67: 243-6.
14. Choi WT, Kaul M, Kumar S, Wang J, Dong CZ, An J, Lipton SA and Huang Z.  Neuronal apoptotic signaling pathways probed and intervened by synthetically and modularly modified (SMM) chemokines.  J. Biol. Chem., 2007, 282:7154-63
15. Liu D, Madani N, Li Y, Cao R, Choi WT, Kawatkar SP, Lim MY, Kumar S, Dong CZ, Russell JD, Lefebure CR, An J, Wilson S, Gao YG, Pallansch LA, Sodroski JG and Huang Z.  Crystal structure and structural mechanism of a novel anti-human immunodeficiency virus and D-amino acid-containing chemokine.   J. Virology, 2007, 81:11489-11498.
16. Zhai D, Jin C, Huang Z, Satterthwait AC, Reed JC.  Differential regulation of Bax and Bak by anti-apoptotic Bcl-2-family proteins, Bcl-B and Mcl-1.  J Biol Chem., 2008, 283: 9580-9586.
17. Wu D, Pang Y, Ke Y, Yu J, He Z, Tautz L, Mustelin T, Ding S, Huang Z and Feng GS. A conserved mechanism for control of human and mouse embryonic stem cell pluripotency and differentiation by shp2 tyrosine phosphatase. PLoS ONE, 4:e4914, 2009.
18. Krieg A, Correa RG, Garrison JB, Negrate GL, Welsh K, Huang Z, Knoefel WT and Reed JC.  XIAP mediates NOD signaling via interaction with RIP2.  Proc. Natl. Acad. Sci. USA, 2009, in press.