INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE DIMERIZATION USING SYNTHETIC PEPTIDES DERIVED FROM THE CONNECTION DOMAIN

Based on presently available information on the structure of human imm unodeficiency virus type 1 (HIV-1) reverse transcriptase, peptides hav e been synthesized which correspond to the sequence of a particular re gion of the protein involved in formation of the active heterodimeric form of the enzyme. Several peptides that are 15-19 amino acids long a nd that are derived from the so called connection domain of the revers e transcriptase are able to inhibit dimerization of the enzyme and thu s inhibit development of its enzymatic activities. In particular, a tr yptophan-rich 19-mer corresponding to residues 389-407 was relatively efficient, showing an apparent dissociation constant in the micromolar range for one or both of the subunits. The sequence of this region is identical for both subunits, since one (molecular mass of 51 kDa) is the proteolytic product of the other (molecular mass of 66 kDa). Disso ciation of the preformed heterodimer could not be induced by the pepti des, but increasing concentrations reduced the rate of dimerization in a concentration dependent manner until it became immeasurable at high concentrations. The results suggest that inhibition of dimerization o f reverse transcriptase is an attractive approach to chemotherapeutic intervention in HIV infection and that further development of peptide based inhibition strategies is worth pursuing.