Inhibition mechanisms of HIV-1, Mo-MuLV and AMV reverse transcriptases by Kelletinin A from Buccinulum corneum.
Kelletinin A [ribity pentakis (p-hydroxybenzoate)] (KA), an inhibitor of HTLV-1 replication isolated from Buccinulum corneum, showed a noncompetitive inhibitory activity with respect to the template primer and to dTTP in the poly(rA).oligo(dT)12-18-directed reaction of HIV-1, Mo-MuLV and AMV reverse transcriptases (RT). Analysis of natural and synthetic KA-related compounds showed that the inhibitory activity was strictly related to the structural peculiarities of the molecule. In the presence of DNA as template primer the inhibition mechanism was drastically modified: HIV-1 RT activity was stimulated by low concentrations of KA and was inhibited by increasing the concentration of the compound, while Mo-MuLV and AMV activities were irreversibly inhibited by the formation of a non-reactive complex. The RNase H activities of these RTs were not affected by KA. The results of this study suggest a different mechanism of interaction of Kelletinins with HIV-1 RT compared with other non-nucleoside inhibitors. A possible use of these drugs in combination therapy and in the design of structure-based reverse transcriptase inhibitors is discussed.
Orlando
P
P
Istituto Biochimica delle Proteine ed Enzimologia, CNR, Arco Felice, Naples, Italy.
Strazzullo
G
G
Carretta
F
F
De Falco
M
M
Grippo
P
P
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D009189:Avian Myeloblastosis Virus / Q000187:drug effects / Q000201:enzymology*; D004279:DNA, Viral / Q000378:metabolism; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D062385:Hydroxybenzoates / Q000494:pharmacology*; D007700:Kinetics; D008974:Mollusca / Q000737:chemistry; D008979:Moloney murine leukemia virus / Q000187:drug effects / Q000201:enzymology*; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D011061:Poly A / Q000378:metabolism; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D012255:Ribitol / Q000031:analogs & derivatives* / Q000494:pharmacology; D016914:Ribonuclease H / Q000378:metabolism; D013698:Templates, Genetic
D000998:Antiviral Agents; D004279:DNA, Viral; D062385:Hydroxybenzoates; D009838:Oligodeoxyribonucleotides; D018894:Reverse Transcriptase Inhibitors; C067618:kelletinin A; D011061:Poly A; D012255:Ribitol; C018368:poly(rA).oligo(dT); D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D016914:Ribonuclease H