RESUMO
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.
Assuntos
Vírus da Mieloblastose Aviária/enzimologia , HIV-1/enzimologia , Hidroxibenzoatos/farmacologia , Vírus da Leucemia Murina de Moloney/enzimologia , DNA Polimerase Dirigida por RNA/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Ribitol/análogos & derivados , Animais , Antivirais/farmacologia , Vírus da Mieloblastose Aviária/efeitos dos fármacos , DNA Viral/metabolismo , Transcriptase Reversa do HIV , HIV-1/efeitos dos fármacos , Cinética , Moluscos/química , Vírus da Leucemia Murina de Moloney/efeitos dos fármacos , Oligodesoxirribonucleotídeos/metabolismo , Poli A/metabolismo , Ribitol/farmacologia , Ribonuclease H/metabolismo , Moldes GenéticosRESUMO
Kelletinin A [ribityl-pentakis (p-hydroxybenzoate)] (KA), a natural compound isolated from the marine gastropod Buccinulum corneum, showed antiviral activity on the human T-cell leukemia virus type-1 (HTLV-1) and antimitotic activity on HTLV-1-infected MT2 cells. KA inhibited cellular DNA and RNA synthesis, without influencing protein synthesis, and interfered with viral transcription by reducing the levels of high molecular weight transcripts. Finally, the compound inhibited HTLV-1 reverse transcriptase in vitro.
Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Divisão Celular/efeitos dos fármacos , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Hidroxibenzoatos/farmacologia , Ribitol/análogos & derivados , Replicação Viral/efeitos dos fármacos , Northern Blotting , Linhagem Celular , Replicação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Hidroxibenzoatos/toxicidade , Biossíntese de Proteínas , RNA/antagonistas & inibidores , RNA/biossíntese , RNA Viral/análise , RNA Viral/biossíntese , DNA Polimerase Dirigida por RNA/metabolismo , Ribitol/farmacologia , Ribitol/toxicidade , Linfócitos TRESUMO
The inhibitory effect of esters of p-hydroxybenzoic acid (kelletinins I and A), extracted from the marine gastropod Buccinulum corneum, have been tested on eukaryotic and prokaryotic enzymes of DNA metabolism such as DNA polymerases alpha and beta, DNA polymerase I, Exo III, pancreatic DNAse I, micrococcal DNAse and E. coli RNA polymerase. Kelletinin I and kelletinin A inhibit preferentially DNA polymerase alpha. The inhibitory effect of kelletinin I involves the hydroxyl group of p-hydroxybenzoic acid.