Selective side-chain modification of cysteine and arginine residues blocks pathogenic activity of HIV-1-Tat functional peptides |
| |
Authors: | Devadas Krishnakumar Boykins Robert A Hardegen Neil J Philp Deborah Kleinman Hynda K Osa Etin-Osa Wang Jiun Clouse Kathleen A Wahl Larry M Hewlett Indira K Rappaport Jay Yamada Kenneth M Dhawan Subhash |
| |
Institution: | Immunopathogenesis Section, Laboratory of Molecular Virology, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike (HFM-315), Rockville, MD 20852-1448, USA. |
| |
Abstract: | 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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|