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Department of Pharmacology

Department of Pharmacology

Richard Horuk, Ph.D.

.
Richard Horuk, Ph.D.

Visiting Professor
Ph.D., University of London, UK, 1980
(916) 734-3661
e-mail


 

Research Interests

Chemokine receptors as therapeutic targets both for autoimmunity and for the treatment of Malaria

Research Synopsis

I have a major interest in discovering small molecule antagonists to chemokine receptors as potential therapeutics to treat autoimmune diseases. While in the pharmaceutical industry I discovered a CCR1 antagonist that progressed as far as phase II clinical trials for the treatment of multiple sclerosis. As part of this continuing research interest I am looking at intervention therapies in malaria. The invasion of human red blood cells by the malaria parasite Plasmodium vivax requires an interaction between a ligand expressed on the surface of the parasite (DBP) with a cell surface receptor expressed on host cell erythrocytes (the Duffy blood group antigen. My laboratory has shown that the Duffy antigen is a chemokine binding protein and we named it Duffy Antigen Receptor for Chemokines, or DARC. A soluble domain of the DBP, as well as peptides from the domain, antibodies against the DBP soluble domain, and chemokines, can all block the binding of the parasite ligand and the invasion of human erythrocytes by P. vivax. Similarly, chemokines and the soluble DBP block erythrocyte invasion by the simian malaria parasite P. knowlesi, which is also dependent on the interaction between the DBP with DARC. These studies provide strong evidence in support of receptor blockade as a strategy for anti-malarial therapy. We envisage that our approach to identify small molecule inhibitors of DARC will prove to be of major benefit in drastically reducing the number of cases of P. vivax malaria via treatment and reduced transmission. Such inhibitors in combination with existing therapies should also delay the emergence and spread of resistance. To achieve our major goal of identifying small molecule antagonists of DARC, we are developing a high-throughput assay in a 384-well format that will be used to screen against an NIH compound library. In addition the assay will also be used to screen against the 700,000 non-proprietary compound collection at the Genomics Institute of the Novartis Research Foundation (San Diego, CA) to identify small molecule inhibitors of DARC.

Selected Publications

Hadley, T., Lu, Z., Wasniowska, K., Martin, A.W., Peiper, S. C., Hesselgesser, J., Horuk, R. (1994) Post-capillary venule endothelial cells in kidney express a multispecific chemokine receptor that is structurally and functionally identical to the erythroid isoform, which is the Duffy antigen J. Clin. Invest. 94, 985-991.

Fairbrother, W.J., Reilly, D., Colby, T.J., Hesselegesser, J. and Horuk, R. (1995) The solution structure of melanoma growth stimulating activity (MGSA) J. Mol. Biol. 242, 252-270.

Peiper, S., Wang, Zi-xuan, Neote, K., Martin, A.W., Showell, H.J., Conklyn, M.J., Ogborne, K., Hadley, T. J., Zhao-hai Lu, Hesselgesser, J. and Horuk, R. (1995) The Duffy antigen/receptor for chemokines (DARC) is expressed in Endothelial cells of Duffy negative individuals, who lack the erythrocyte receptor J. Exp. Med. 181, 1311-1317.

 Hesselgesser, J., Chitnis, C., Miller, L., Yansura, D.J., Simmons, L., Fairbrother, W., Kotts, C., Wirth, C., Gillece-Castro, B. and Horuk, R. (1995) Alanine scanning mutagenesis of MGSA identifies specific amino acids that bind to the Duffy antigen/chemokine receptor and the type B IL-8 receptor. J. Biol. Chem. 270, 11472-11476.

Zhao-hai, L., Horuk, R., Zi-xuan, W., Hesselgesser,J., Yan-chun, L., Hadley,T.J. and Peiper S.C. (1995) The Promiscuous Chemokine Binding Repertoire of the Duffy Antigen/Receptor for Chemokines (DARC) is Primarily Localized to Sequences in the Amino Terminal Domain J. Biol. Chem. 270, 26239-26245.

Liu, R., Paxton, W. A., Choe, S., Ceradini, D., Martin, S. R., Horuk, R., MacDonald, M. E., Stuhlmann, H., Koup, R.A., and Landau, N.R. (1996) Homozygous Defect in HIV-1 Coreceptor Accounts for Resistance of Some Multiply-Exposed Individuals to HIV-1 Infection Cell 86, 367-377.

Chitnis, C.E., Chaudhri, A., Horuk, R., Pogo, A.O. And Miller, L.H. (1996) The domain on the Duffy blood group Antigen for binding Plasmodium vivax and P. Knowlesi malarial parasites to erythrocytes (1996) J. Exp. Med. 184, 1531-1536.

Haribabu, B., Richardson, R. M., Fisher, I., Sozzani, S., Peiper, S.C., Horuk, R., Ali, H., and Snyderman, R. (1997) Regulation of human chemokine receptor CXCR4: Role of phosphorylation in desensitization and internalization J. Biol. Chem. 272, 28726-28731.

Hesselgesser, J., Ng, H., Liang, M., Monahan, S., Islam, I., Wei, G.P., Ghannam, A., Li, A., Rosser, M., Snider, M., Morrissey, M., Perez, H.D. and Horuk, R. (1998) Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor J. Biol. Chem. 273, 15687-15692.

Barnes, D.A., Tse, J., Kaufhold, M., Owen, M., Hesselgesser, J., Streiter, R., Horuk, R., and Perez, H.D. (1998) Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model J. Clin. Invest. 101, 2910-2919.

Liang, M., Mallari, C., Rosser, M., Ng, H., May, K., Monahan, S., Bauman, J.G., Islam, I., Ghannam, A., Buckman, B., Shaw, K., Wei, G.P., Xu, W., Zhao, Z., Ho, E., Oanh, H., Subramanyam, B., Vergona, R., Taub, D., Dunning, L., Harvey, S., Snider, M., Hesselgesser, J., Morrissey, M., Perez, H.D., and Horuk, R. (2000) Identification and Characterization of a Potent, Selective and Orally Active Antagonist of the CC Chemokine Receptor-1 J. Biol. Chem. 275,19000-19008.

Horuk, R., Clayberger, C., Krensky, A.M., Wang, Z., Weber, C., Weber, K.S.C., Nelson, P.J., May, K., Buckman, B., Ghannam, A., Ng, H.P., Islam, I., Bauman J.G., Wei, G-P., Monahan, S., Xu, W., Rosser, M., Dunning, L., Liang, M., Snider, R.M., Morrissey, M.M., Hesselgesser, J., and Perez, H.D. (2001) Non-peptide functional antagonists of the CCR1 chemokine receptor are effective in rat heart transplant rejection J. Biol. Chem. 276, 4199-4204.

Anders, H.J., Vielhauer, V., Frink, M., Linde, Y., Cohen, C.D., Blattner, S., Kretzler, M., Strutz, F., Mack, M., Gröne, H.J., Horuk, R., Nelson, P.J. and Schlöndorff, D. (2002) A chemokine receptor-1-specific non-Peptide antagonist reduces established renal fibrosis after unilateral ureter obstruction J. Clin. Invest. 109, 251-259.

Futamatsu, H., Suzuki, J., Koga,N., Adachi,S., Kosuge, H., Maejima, Y., Haga, T.,, Hirao, K., Horuk, R., Isobe, M. (2006) A CCR1 Antagonist Prevents the Development of Experimental Autoimmune Myocarditis in Association with T Cell Inactivation Journal of Molecular and Cellular Cardiology 40. 853-861.

Vaidehi, N., Schlyer, S., Trabanino, R., Kochanny, M., Abrol, A., Koovakat, S., Dunning, L., Liang, M., Sharma, S., Fox, J., Floriano, W. B., de Mendonça, F.L., Pease, J., Goddard III, W.A., and Horuk, R. (2006) Predictions of CCR1 Chemokine receptor structure and BX 471 Antagonist binding followed by experimental validation J. Biol. Chem. 281, 27613-27620.

Horuk, R. (2009) Chemokine receptor antagonists:Overcoming developmental hurdles Nature Reviews in Drug Discovery 8, 22-33.

See: Complete List of Publications