HIV-1 RT inhibition

Two novel alkaloids named manadomanzamines A and B were isolated from the Indonesian sponge Acanthostrongylophom spp. [58]. The compounds exhibited activities against HIV-1 and AIDS-opportunistic fungal infections. Oral and intravenous pharmacokinetic studies indicated that the compounds have low metabolic clearance, a reasonably long pharmacokinetic half-life, which supports the value of these compounds as potential leads for further preclinical assessment and possible development [59]. Another marine sponge, Petrosia similis, afforded two compormds belonging to bis-quinolizidine alkaloids, namely petrosin and petrosin A [60]. Cell assays indicated that these compounds inhibited the early steps of HIV replication. In the extracellular HIV-1 RT inhibition assay, the compounds inhibited HIV-1 RT. 

A recent example is the substrate analogue thymidine 5 -[a,P-iaiido]triphosphate [141171-20-2] (TMPNPP) (2) which competitively inhibits the human iaimunodeficiency vims-1 (HIV-1) reverse transcriptase (HIV-1 RT) with a iC value of 2.4 micromolar ]lM) (9). The substrate is thymidine 5 -triphosphate... 

Although the NNRTIs target HIV-1 RT, they are clearly different from the nucleoside RT inhibitors (NRTIs). They are highly selective for HlV-1 and do not inhibit HlV-2 or any other retrovirus. Moreover, the resistance spectrum of NNRTIs is different from that of NRTI, and, as a rule, NRTl-resistant mutant virus strains keep full sensitivity to the inhibitory effects of NNRTIs, and NNRTI-resistant mutant virus strains keep full sensitivity to the inhibitory effects of NRTIs. However, some influence of NRTI mutations on NNRTl susceptibility has been observed (Shuhnan etal. 2004). 

The first NNTRI drug candidate 2 was selected for development in 1992. Compound 2 exhibits very potent antivirus activity of IC50 = 12nM (inhibition HIV-1 RT using rC-dG template/primer). The Medicinal Chemistry original preparation route is depicted in Scheme 1.1 [2]. 

Yet other compounds have been found to inhibit HIV-1 replication through a specific interaction with HIV-1 RT (i.e., quinoxaline S-2720 [68], 5-chloro-3-(phenylsulfonyl)indole-2-carboxamide [69], dihydrothiazolo-isoindolones [70] and a number of natural substances (e.g., calanolide A and inophyllums, from the tropical rain forest trees Calophyllum lanigerum and Calophyllum inophyllum, respectively) [71,72]. All these and yet other compounds could be considered to be NNRTIs. The most potent among the NNRTIs, some of the HEPT derivatives (E-EBU-dM) [63] and a-... 

Based on structural, biochemical, and genetic data several hypotheses have been postulated about the mechanism(s) of inhibition of HIV-1 RT by NNRTIs. It is... 

A series of natural products, i.e., trihydroxyquinolone compounds isolated from Red Sea marine organisms, were reported to inhibit the DNA polymerase activity of HIV-1 RT [124,125]. This type of inhibitor appears to have a mechanism of inhibition that is different from either the NRTI inhibition mechanism or the NNRTI inhibition mechanism. The inhibition is reversible and noncompetitive with respect to both dNTP and template-primer [125]. This result indicates that there are other potential binding sites for inhibitors of HIV-1 RT. 

Two saponins from soybean seeds having soyasapogenol as aglycone were shown to have a partial inhibitory effect on HIV-induced cytopathology in infected human MT-2 lymphocytes cultures [158], The major constituent of group of B saponins from soybean seeds completely inhibited HIV-induced cytophatic effects and virus-specific antigen expression 6 days after infection at concentration > 0.25 mg/ml. Saponins isolated from soybean seeds inhibited HIV-1 replication in MT-4 cells at 0.5 [tg/ml (Nakamura et al. 1992) [159]. These saponins had a narrow therapeutic index and did not inhibit HIV-1 RT. One of them was found to inhibit HIV-induced cell fusion in MOLT-4 cells. 

A single-stranded DNA library was also screened against the HIV-1 RT. IQ values for the selected DNA sequences were in the nanomolar range and they inhibited the DNA polymerase activity of this enzyme with a K, as low as 1 nM (Schneider et al., 1995). The best DNA aptamer folds as a hairpin with an internal loop and competes with the RNA pseudo-knot for RT binding. These two ligands share very little structural similarity. 

HIV-1 RT HIV-2 RT [antiviral, HIV inhibition, inhibits cellular formation syncytium formation]... 

Arctigenin Ipomoea cairica (Convolvulaceae) HIV-1 RT [metabolites inhibit... 

HIV-1 RT RNase H [weak antitrypanosomal anti-plasmodial] HIV-1 RT (84nM) [inhibits HIV-1 replication (40nM)] [Metabolic conversion to the nucleoside triphosphate (NTP) (or equivalent) and RT-catalysed incorporation into DNA of the NMP (or equivalent) gives DNA chain termination because of the absence of a 3 -hydroxyl]... 

Kinetic analysis demonstrated that (+)-calanolide A inhibited HIV-1 RT by a complex mechanism involving two possible binding sites one of the calanolide binding sites is near both the pyrophosphate binding site and the active site of the RT enzyme. ... 

The side chain at position-28 is critical for the antifusion activity of the BA derivatives, whereas a dimethylsuccinyl acid at position-3, as in DSB (263), results in inhibition of viral maturation rather than affecting the envelope-mediated membrane fusion. The key structural feature that enables LH55 (283) and its analogs to possess a dual mode of action is the presence of side chains at both C-3 and C-28. The unique biological activity of these compounds is that they not only inhibit viruses that are resistant to HIV-1 RT and PR inhibitors, but also they inhibit vimses that are resistant to compounds with side chains only at position-3 or... 

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