PMID- 7532006 OWN - NLM STAT- MEDLINE DCOM- 19950322 LR - 20190613 IS - 0006-2960 (Print) IS - 0006-2960 (Linking) VI - 34 IP - 7 DP - 1995 Feb 21 TI - Mechanism of inhibition of HIV reverse transcriptase by toxiusol, a novel general inhibitor of retroviral and cellular DNA polymerases. PG - 2260-6 AB - Toxiusol, a natural product isolated from the Red Sea sponge Toxiclona toxius, has been shown to be a potent inhibitor of various viral reverse transcriptases (RT) [i.e., of human immunodeficiency virus (HIV-1), equine infectious anemia virus, and murine leukemia virus] and cellular DNA polymerases (i.e., of DNA polymerases alpha and beta and Escherichia coli DNA polymerase I). A thorough investigation of the mode of inhibition was conducted with HIV-1 RT-associated DNA polymerase activity. The inhibition is unaffected by the nature of template-primer used. The inhibitory active site of toxiusol is attributable to the polar moieties at the benzene ring. The presence of either sulfate groups in the natural lead compound or hydroxyl groups in the corresponding hydroquinone is critical, because both compounds are equally effective at low micromolar concentrations. Conversely, the presence of acetyl groups in the same position in the derivative toxiusol diacetate lowers significantly or abolishes the inhibitory activity. Toxiusol binds the HIV-1 RT irreversibly and in a noncompetitive way with high affinity (Ki = 1.2 microM), probably through polar groups. The replacement with acetyl moieties in the analog toxiusol diacetate hampers the binding of the inhibitor to the enzyme (Ki increases to about 26 microM). Still, the compound binds irreversibly, probably through its hydrophobic structure skeleton. Toxiusol diacetate loses its ability to inhibit the first step in the DNA polymerization process (that is, the formation of the DNA-enzyme complex as measured by a gel retardation assay), which contributes to its poor inhibitory capacity.(ABSTRACT TRUNCATED AT 250 WORDS) FAU - Loya, S AU - Loya S AD - Department of Cell Biology, Sackler School of Medicine, Tel Aviv, Israel. FAU - Bakhanashvili, M AU - Bakhanashvili M FAU - Kashman, Y AU - Kashman Y FAU - Hizi, A AU - Hizi A LA - eng GR - AI31790/AI/NIAID NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Biochemistry JT - Biochemistry JID - 0370623 RN - 0 (Hydroquinones) RN - 0 (Nucleic Acid Synthesis Inhibitors) RN - 0 (Reverse Transcriptase Inhibitors) RN - 0 (Tetrahydronaphthalenes) RN - 0 (toxiusol) RN - EC 2.7.7.49 (HIV Reverse Transcriptase) SB - IM MH - Animals MH - HIV Reverse Transcriptase MH - HIV-1/enzymology MH - Hydroquinones/*pharmacology MH - Kinetics MH - Nucleic Acid Synthesis Inhibitors MH - Porifera/*chemistry MH - *Reverse Transcriptase Inhibitors MH - Species Specificity MH - Templates, Genetic MH - Tetrahydronaphthalenes/*pharmacology EDAT- 1995/02/21 00:00 MHDA- 1995/02/21 00:01 CRDT- 1995/02/21 00:00 PHST- 1995/02/21 00:00 [pubmed] PHST- 1995/02/21 00:01 [medline] PHST- 1995/02/21 00:00 [entrez] AID - 10.1021/bi00007a021 [doi] PST - ppublish SO - Biochemistry. 1995 Feb 21;34(7):2260-6. doi: 10.1021/bi00007a021.