TETRAHYDROPYRIMIDINE DERIVATIVES INHIBIT BINDING OF A TAT-LIKE, ARGININE-CONTAINING PEPTIDE, TO HIV TAR RNA IN-VITRO

The ability of a small molecule, l,4-carboxy,5-hydroxy-3,4,5,6-tetrahy dropyrimidine (THP(A)), which accumulates intracellularly in various s treptomyces, to inhibit the interaction of Tat peptide (R52) with TAR RNA is presented. Using gel-shift assay, we found that the inhibition constant Ki of THP(A) is 50-100 nM, which is in the range of the bindi ng constants of Tat peptide and protein. THP(A) is similar to 10(6) ti mes more tightly bound than the free L-arginine. The high binding affi nity may be attributed to the special delocalized positive charge on t he NCN group and the hydroxyl group at the 5 position of this molecule . A model for THP(A)-TAR interaction, analogous to the arginine guanid inum group-TAR interaction, is presented. The relatively high uptake o f THP(A) by mammalian cells warrants in who Tat/TAR inhibition studies .