Tetrahydropyrimidine derivatives inhibit binding of a Tat-like, arginine-containing peptide, to HIV TAR RNA in vitro

FEBS Letters
A LapidotM Eisenstein

Abstract

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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Citations

Jun 16, 2009·Neurotoxicity Research·Wenxue LiAvindra Nath
Mar 10, 2004·Bioorganic & Medicinal Chemistry Letters·Mickaël MontembaultJacques Lebreton
May 17, 2003·Bioorganic & Medicinal Chemistry Letters·Tomoko HammaPaul S Miller
Apr 15, 2003·Antisense & Nucleic Acid Drug Development·Tomoko Hamma, Paul S Miller
Feb 24, 1998·Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology : Official Publication of the International Retrovirology Association·I ChoudhuryM J Leibowitz
Jul 6, 2010·Biotechnology Advances·José M PastorManuel Cánovas
Jun 23, 2004·Biochemical and Biophysical Research Communications·Hong ZhaoLong Jiang
Dec 30, 2016·Arhiv za higijenu rada i toksikologiju·Adam Bownik, Zofia Stępniewska
Mar 18, 1999·Antiviral Chemistry & Chemotherapy·D DaelemansE De Clercq
Apr 6, 2004·FEBS Letters·Hong ZhaoLong Jiang
May 16, 2009·Chembiochem : a European Journal of Chemical Biology·Jan FernerHarald Schwalbe
Dec 23, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Lukas Bethlehem, Gerhild van Echten-Deckert

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