Development of Prothymosin-Alpha-Derived anti-HIV Agents Grant uri icon

abstract

  • A major challenge encountered in the treatment of human immunodeficiency virus (HIV) is the emergence of drug-resistant virus strains. Thus, the continued development of new types of anti-retroviral compounds with different mechanisms of action is an important goal. In 2003, the peptide-based drug enfuvirtide (brand name Fuzeon?) was approved by the Food and Drug Administration as an anti-HIV medicine. This drug is the first example of an anti-HIV agent that inhibits the HIV virus from fusing with a host cell's membrane, thus blocking viral entry and infection. Recent work has shown that the protein prothymosin-a (ProTa) has potent HIV inhibitory activity in macrophages. ProTa is an acidic nuclear protein made up of 110 amino acids. The precise function of this protein is unclear, however evidence suggests it is associated with cell proliferation. ProTa has a high level of expression in a wide variety of cell types and tissues and has a high level of evolutionary conservation all the way from yeast to humans. Much of the anti-HIV activity of ProTa can be attributed to the central segment of the protein as a peptide encompassing residues 50-89 possesses significant inhibitory ability as well. The unusual nature of this protein, specifically the high occurrence of acidic residues and the lack of secondary structure, leads us to believe that it may have a completely different mechanism of action than existing agents. Further, its peptidic nature should insure that is has a very low toxicity. This research proposal has two objectives based on using ProTa-derived sequences: 1) Determine if exogenously applied ProTa enters the cell and track where it localizes and 2) Determine the features of the sequence that are required for anti-HIV activity. Completion of these objectives will allow us to design improved anti-1llV agents and we envision their use as injectable or topical agents that reduce viral replication and the transmission of viral infection. Further, these constructs will serve as tools to further investigate cellular mechanisms for the suppression of viral replication. All peptides will be designed and synthesized by the PI's lab and the anti-1llV activity studies will be carried out by our collaborators Dr. Arevik Mosoian and Dr. Mary Klotman at the Mount Sinai School of Medicine.

date/time interval

  • July 2008 - December 2009