Tetrahydropyrimidine derivatives inhibit binding of a Tat-like, arginine-containing peptide, to HIV TAR RNA in vitro.
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.
Lapidot
A
A
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Ben-Asher
E
E
Eisenstein
M
M
D001426:Bacterial Proteins / Q000378:metabolism*; D001483:Base Sequence; D002628:Chemoreceptor Cells; D029968:Escherichia coli Proteins; D015696:Gene Products, tat / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008956:Models, Chemical; D008969:Molecular Sequence Data; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D012329:RNA, Bacterial / Q000378:metabolism; D011956:Receptors, Cell Surface; D014779:Virus Replication / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D015696:Gene Products, tat; D008565:Membrane Proteins; D011743:Pyrimidines; D012329:RNA, Bacterial; D011956:Receptors, Cell Surface; C057331:Tar protein, E coli; D054322:tat Gene Products, Human Immunodeficiency Virus; C081912:2-methyl-4-carboxy-5-hydroxy-3,4,5,6-tetrahydropyrimidine