A Novel Class of Glycoconjugates to Prevent HIV Entry
Mark A. Witschi, University of California, Davis
Human Immunodeficiency Virus (HIV) infects human T-cells through the recognition of envelope glycoprotein gp120 by the membrane CD4 receptor. This interaction initiates a conformational change in gp120, which allows for further interaction of gp120 with a chemokine co-receptor, either CXCR4 or CCR5. Subsequent changes in the conformation of gp120 allow for a HIV-fusion peptide (gp41) to anchor into the host cell membrane. At this point, the virus has fused with the host cell, the glycoproteins are lost, and the genetic material enters the host cell. The initial interaction of the CD4 receptor with gp120 affords an interesting target for HIV therapy. The interface of the gp120 and CD4 complex has been widely studied and analysis affords pertinent structural information. Two amino acids, a phenylalanine and an arginine residue, have been shown to be imperative to the recognition of gp120 by the CD4 receptor. A novel class of glycoconjugates, intended to mimic the gp120-binding pocket of CD4, is described. The glycoconjugates contain a tetra-mannose scaffold, non-natural ether linkages, and the necessary phenylalanine and arginine amino-acid residues. The proposed research describes the synthetic routes and methods that will be utilized to prepare a glycoconjugate library designed for inhibition of HIV entry. The goals to be met with this project are two-fold. First, the efficient synthesis of glycoconjugates on solid-support will allow for the timely production of a variety of glycoconjugates. Second, the screening of a glycoconjugate library for binding to gp120 by numerous biological assays will be investigated. The systematic modification of the amino-acid side-chains will reveal the importance of numerous factors, such as stereochemistry and functional group tolerance, on binding gp120. The information gained from initial results will allow for libraries to be efficiently prepared based on structure-activity relationships, producing potent inhibitors of HIV entry.