title: Inhibition of tat-mediated HIV-1-LTR transactivation and virus replication by sulfhydryl compounds with chelating properties.
abstract: D-Penicillamine, a structural analog of cysteine, has the ability to chelate metal ions and reacts with cysteine. We have shown earlier that D-Penicillamin is a potential inhibitor of tat-mediated transactivation of HIV-1-LTR (14) and possesses anti-HIV-1 activity (23). Following this approach, we evaluated the anti-tat and anti-HIV-1 activity of several sulfhydryl compounds with chelating properties. The tested compounds: N-(2-Mercapto-propionyl)-glycin (MPG), 2,3-Dimercapto-propanol (DMP) and 2,3-Dimercapto-propane-sulfonic acid (DMPS) exhibited an inhibitory effect on the tat-mediated transactivation in Jurkat cells, as well as in U937 cells. The highest inhibitory response was shown by DMP leading to about 50% inhibition of transactivation in Jurkat cels and an 80% inhibition in U937 cells. On the contrary, DMPS (30 micrograms/ml) had no inhibitory effect in U937 cells, but did exhibit a 50% inhibition of transactivation in Jurkat cells at 30 micrograms/ml. The antiviral activity of DMP and DMPS was evaluated in H9 cells. In the concentration range which is effective for antiviral effect, both the compounds were highly cytotoxic. Mercapto-propionyl-glycin, although a weak inhibitor of transactivation, was able to inhibit synctia formation to more than 90% and inhibit the viral antigene expression to about 70%. The concentration of MPG needed to achieve this antiviral effect was very high, but it had no cytotoxicity at this concentration. We suggest that a search for compounds using this approach may be useful in developing potential inhibitors of tat-mediated transactivation.
authors.affiliation: Gustav-Embden Center, Department of Molecular Biology, Frankfurt University Medical School, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Demirhan
authors.forename: A
authors.initials: A
authors.lastname: Chandra
authors.forename: P S
authors.initials: PS
authors.lastname: Sarin
authors.forename: O
authors.initials: O
authors.lastname: Hasselmayer
authors.forename: D
authors.initials: D
authors.lastname: Hofmann
authors.forename: P
authors.initials: P
authors.lastname: Chandra
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002614:Chelating Agents / Q000494:pharmacology*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors*; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*; D020298:U937 Cells; D014779:Virus Replication / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D019380:Anti-HIV Agents; D002614:Chelating Agents; D015696:Gene Products, tat; D013438:Sulfhydryl Compounds; D054322:tat Gene Products, Human Immunodeficiency Virus