Key result
THP-A inhibits HIV Tat-TAR RNA interaction in vitro, binding ~1 million times tighter than free L-arginine.
Why the study?
The ability of small molecules to inhibit the interaction of Tat peptide with HIV TAR RNA and their binding affinity compared to free L-arginine was investigated.
Does THP(A) inhibit the interaction of Tat peptide with HIV TAR RNA in vitro?
Does THP(A) inhibit the interaction of Tat peptide with HIV TAR RNA in vitro?
THP(A) demonstrates high-affinity inhibition of Tat peptide binding to HIV TAR RNA in vitro, suggesting potential for in vivo Tat/TAR inhibition studies.
Hypothesis-generating for Tat-TAR antivirals; leaves open translation from in vitro potency to cellular or clinical efficacy.
The ability of a small molecule, 2-methyl,4-carboxy,5-hydroxy-3,4,5,6-tetrahydropyrimidine (THP(A)), which accumulates intracellularly in various streptomyces, 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 binding constants of Tat peptide and protein. THP(A) is approximately 10(6) times more tightly bound than the free L-arginine. The high binding affinity may be attributed to the special delocalized positive charge on the NCN group and the hydroxyl group at the 5 position of this molecule. A model for THP(A)-TAR interaction, analogous to the arginine guanidinum group-TAR interaction, is presented. The relatively high uptake of THP(A) by mammalian cells warrants in vivo Tat/TAR inhibition studies.
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Lapidot et al. (1995) studied HIV. 2-methyl,4-carboxy,5-hydroxy-3,4,5,6-tetrahydropyrimidine (THP(A)) vs. free L-arginine was evaluated on Inhibition constant (Ki) for Tat peptide-TAR RNA interaction. THP(A) inhibited the interaction of Tat peptide with HIV TAR RNA in vitro with an inhibition constant (Ki) of 50-100 nM, binding approximately 10^6 times more tightly than free L-arginine.