Scientific Publications by FDA Staff
Peptides 2006 Apr;27(4):611-21
Selective side-chain modification of cysteine and arginine residues blocks pathogenic activity of HIV-1-Tat functional peptides.
Devadas K, Boykins RA, Hardegen NJ, Philp D, Kleinman HK, Osa EO, Wang J, Clouse KA, Wahl LM, Hewlett IK, Rappaport J, Yamada KM, Dhawan S
Dhawan S, US FDA, Ctr Biol Evaluat & Res, Mol Virol Lab, Immunopathogenesis Sect, 1401 Rockville Pike HFM-315, Rockville, MD 20852 USA US FDA, Ctr Biol Evaluat & Res, Mol Virol Lab, Immunopathogenesis Sect, Rockville, MD 20852 USA US FDA, Ctr Biol Evaluat & Res, Biophys Lab, Rockville, MD 20852 USA Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, Cellular Immunol Sect, NIH, Bethesda, MD 20892 USA Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA US FDA, Ctr Drug Evaluat & Res, Cell Biol Lab, Bethesda, MD 20892 USA Natl Inst Dent & Craniofacial Res, Immunopathol Sect, NIH, Bethesda, MD 20892 USA Temple Univ, Ctr Neurovirol & Canc Biol, Philadelphia, PA 19122 USA
Extracellular Tat protein of HIV-1 activates virus replication in HIV-infected cells and induces a variety of host factors in the uninfected cells, some of which play a critical role in the progression of HIV infection. The cysteine-rich and arginine-rich basic domains represent key components of the HIV-Tat protein for pathogenic effects of the full-length Tat protein and, therefore, could be ideal candidates for the development of a therapeutic AIDS vaccine. The present study describes selective modifications of the side-chain functional groups of cysteine and arginine amino acids of these HIV-Tat peptides to minimize the pathogenic effects of these peptides while maintaining natural peptide linkages. Modification of cysteine by introducing either a methyl or t-butyl group in the free sulfhydryl group and replacing the guanidine group with a urea linkage in the side chain of arginine in the cysteine-rich and arginine-rich Tat peptide sequences completely blocked the ability of these peptides to induce HIV replication, chemokine receptor CCR-5 expression, and NF-kappaB activity in monocytes. Such modifications also inhibited angiogenesis and migration of Kaposi's sarcoma cells normally induced by Tat peptides. Such chemical modifications of the cysteine-rich and arginine-rich peptides did not affect their reactivity with antibodies against the full-length Tat protein. With an estimated 40 million HIV-positive individuals worldwide and approximately 4 million new infections emerging every year, a synthetic subunit HIV-Tat vaccine comprised of functionally inactive Tat domains could provide a safe, effective, and economical therapeutic vaccine to reduce the progression of HIV disease.
|Category: Journal Article, Peer|
|PubMed ID: #16256245|
|Includes FDA Authors from Scientific Area(s): Biologics, Drugs|
|Entry Created: 2011-10-04||Entry Last Modified: 2012-08-29|