Mechanism of inhibition of reverse transcriptase by quinone antibiotics. II. Dependence on putative quinone pocket on the enzyme molecule.

Abstract

Inhibition of avian myeloblastosis virus (AMV)reverse transcriptase by natural and synthetic quinones including antibiotics could be accounted for by an oxidation-reduction reaction. The quinones were shownto function as electron acceptors as revealed by the catalytic oxidation of NADHby Clostridium kluyveri diaphorase which was in excellent agreement with enzyme inhibition activity.The kinetics of inhibition of AMVreverse transcriptase by three synthetic quinones with different core structures, i.e., 6-methoxy-5,8-dihydroquinoline-5,8-dione, 5,8-dihydroisoquinoline-5,8-dione and 1 ,4-naphthoquinone, were studied. These quinones inhibited reverse transcriptase in the same manner as streptonigrin (STN) and were shown to act at a single class of reaction site(s) on the enzyme molecule. In contrast, the quinones with bulky substituents, i.e. , 7-(2-nitrophenethylamino)-5,8-dihydroisoquinoline-5,8-dione and 7-methoxy-6-methyl-3-piperidino-5,8-dihydroisoquinoline-5,8-dione, were inactive as inhibitors of reverse transcriptase, whereas they retained competent catalytic activities in the oxidation of NADHby C. kluyveri diaphorase. Based on these observations, the existence of a specific site of interaction on the enzymemolecule, referred to as a quinone pocket, was proposed. The quinone pocket might play a crucial role in the early sequence of events leading to the inhibition of reverse transcriptase by quinones including STN and sakyomicin A (SKM). Access of SKMto a quinone pocket might be restricted due to its bulky structure in the vicinity of the quinone group. This is inferred from unsuccessful inhibition of reverse transcriptase by the quinones with bulky substituents, resulting in much poorer inhibition of reverse transcriptase in spite of more potent electron acceptor activity in the oxidationreduction system as comparedwith those of STN. STNshowed specificity for AMVreverse transcriptase in comparison with calf thymus DNAdependent DNApolymerase (DDDP) alpha and Escherichia coli DDDPI3). By using various quinones, the importance of the role of the quinone group in the biological activities of STN and good correlation between electron acceptor activities in the oxidation of NADH by Clostridium kluyveri diaphorase and inhibitory activities against AMV reverse transcriptase were reported previously4~6). Depending on these observations, the specificity shown by STNare considered to derive from the

Novel .BETA.-Lactam Antibiotics Synthesized by Amination of Catechols Using Fungal Laccase

“…This is an important indication for the quinonoid character of 3a to 3e, confirming the oxidation of catechols to quinones similar to the hybrid dimer quinones formed from 2,5-dihydroxybenzoic acid derivatives with penicillins, 2) amino acids, 26) and primary aromatic amines, 27,28) and for the hybrid dimer quinones produced from 3,4-dichloraniline with protocatechuic acid and syringic acid. 24,29) Although 3a to 3e have quinone units as an element of the C-7 or C-6 substituent instead of catechol units these products should also have biological activity because of the described activities of other ortho-quinonoid [30][31][32] or para-quinonoid [33][34][35] substances. Biological Activity of the Biotransformation Products Growth inhibition of the new b-lactam antibiotics 3a to 3e against Gram positive strains was determined by the agar diffusion method according to Burkhardt,36) and the results for selected strains-among them multidrug resistant Staphylococcus and Enterococcus strains-are summarized in Table 2.…”

Antitumour Quinones

“…Because of that these quadruplex structures are considered to be promising targets for drug Many different approaches have been undertaken to inhibit telomerase activity up to now, for instance the design of antisense oligonucleotides or nucleoside analogue reverse transcriptase inhibitors [239]. Among the quinones some antibiotics such as streptonigrin and sarkomycin, A were shown to inhibit reverse transcriptase units of retroviral telomerase [240,241]. Interesting structures with strong human telomerase inhibitory effects in a modified telomeric repeat amplification protocol (TRAP) are found among the rubromycins (76)- (79), quinoid compounds containing benzofuran and benzodipyran rings forming spiroketals [242].…”

Novel Ionophores Active against La Crosse Virus Identified through Rapid Antiviral Screening

“…Dasatinib has previously been described to inhibit dengue virus and HIV infection (29,30). Quininone has activity against enterovirus proteases as well as reverse transcriptases (31,32). As mentioned previously, mitoxantrone was identified in a screen for anti-RVFV molecules (16).…”