Go to research details of CBB faculty:
Prof. Rabi Ann Musah
Prof. Li Niu
Prof. Ramaswamy H. Sarma
Prof. Charles Scholes
Rabi Musah Laboratory
Assistant Professor of Chemistry,
Ph.D., 1995, University of Arkansas,Postdoctoral Fellow: The Scripps Research Institute (1994 - 1998)
ph: 518-437-3740; fx: (518) 437-3741;
A major focus of our research program is the development of new therapeutic strategies to combat HIV-1 and HIV-2 pathogenesis and infection. The ability of HIV-1 to promiscuously mutate and still remain infectious has thwarted attempts at therapeutic management using compounds that specifically target reverse transcriptase and protease, both of which are able to maintain function despite significant changes in their amino acid sequences. The manifestation of this mutability has been the development of drug resistant viral strains and the clinical failure of current treatment strategies. In addition, long-term clinical effectiveness of approved anti-HIV drugs has been hampered by issues of patient compliance, drug toxicity, expense, and the presence of latent reservoirs of virus. Thus, the mutationally intolerant retroviral zinc finger domain of the HIV-1 nucleocapsid protein (NCP) represents a more attractive target for antiviral therapy due to its extreme conservation and its obligatory functions in both the early and late phases of viral infection. In addition, given the recent success of combined therapy that targets both reverse transcriptase and protease simultaneously, it is probable that the inclusion of a third mutationally intolerant target might serve to increase the overall effectiveness of this treatment strategy.
The NCP is a small basic protein with two copies of a highly conserved non-classical C-X2-C-X4-H-X4-C (CCHC) sequence (where X is a less conserved amino acid) known as a zinc finger. Each of the two zinc finger domains tightly coordinates one zinc stoichiometrically with three cysteine thiols and a histidine imidazole group, and folds into a stable structure. Findings from mutational studies on virus infectivity highlight the participation of the NCP7 in multiple activities during both early (reverse transcription and integration) and late (protease processing and genomic RNA selection) stages of HIV-1 replication. The essential roles of these highly conserved retroviral zinc fingers in the HIV-1 replication cycle make them choice antiviral targets. We are designing and synthesizing inhibitors of NCP that may ultimately serve as clinically useful drugs. This effort involves the screening of candidate inhibitor compounds using a fluorescence assay, computer modeling to design inhibitor compounds of increased specificity, and organic synthesis. In addition, we are attempting to crystallize the protein in order to obtain an x-ray crystal structure. We are also interested in the biophysical properties of other retroviral zinc finger proteins in general. To characterize these biophysical properties, we employ EPR using zinc finger proteins that contain EPR active labels, and other spectroscopic and kinetic techniques.
The targeting of retroviral nucleocapsid proteins as a management strategy in the control of disease is a new and emerging area. However, the ramifications of this approach are far reaching, particularly since this strategy can be applied to retroviral diseases other than HIV-1, including a variety of leukemias and breast cancers whose etiology is believed to be retroviral. In addition, success in this endeavor may serve as a model for manipulating other types of zinc finger proteins. Sample targets could include transcription factors for anti-tumor therapeutics, microbial and parasite zinc finger proteins for treatment of those infections. Thus, in addition to the potential for therapeutic advances in the treatment of HIV infection, the applications of this methodology represent a promising avenue of exploration and future drug development in other disease states.
A second research focus is in the isolation, analysis, biological evaluation and structure elucidation of natural products from medicinally important plants. Specifically, we are interested in the rational evaluation of folkloric, ethnomedical, and traditional medicinal plants from the Amazon and West African rainforest areas, particularly those having anticancer, anti-microbial and anti-HIV properties.
- Musah, R. A., Jensen, G. M., Bunte, S. W., Rosenfeld, R. J., Goodin, D. B. "Artificial Protein Cavities as Specific Ligand-Binding Templates: Characterization of an Engineered Heterocyclic Cation Binding Site that Preserves the Evolved Specificity of the Parent Protein." Submitted to Biochemistry.
- Kubec, R., Musah, R. A. "Cysteine Sulfoxide Derivatives in Petiveria Alliacea." Submitted to Phytochemistry.
- Jourdheuil, D., Jourdheuil, F. L., Kutchukian, P. S., Musah, R. A., Wink, D. A., Grisham, M. B. "Reaction of Superoxide and Nitric Oxide with Peroxynitrite. Implications for Peroxynitrite-Mediated Oxidation Reactions In Vivo." Submitted to Journal of Biological Chemistry
- Cao, Y., Musah, R.A., Wilcox, S.K., Goodin, D.B. & McRee, D.E. (1998) "Protein Conformer Selection by Ligand Binding Observed with Crystallography" Protein Science. 7, 72-78.
- Musah, R.A., Jensen, G.M., Rosenfeld, R.J., Bunte, S.W., McRee, D.E. & Goodin, D.B. (1997) "Variation in Strength of a CH to O Hydrogen Bond in an Artificial Cavity" J. Am. Chem. Soc. 119, 9083-9084.
- Musah, R.A., McRee, D.E. & Goodin, D.B. (1997) "Introduction of Novel Substrate Oxidation into a Heme Peroxidase by Cavity Complementation: Oxidation of 2-aminothiazole and Covalent Modification of the Enzyme" Biochemistry 36, 11665-11674.