The Compound 6-Chloro-1,4Dihydro4Oxo1-(β-D-Ribofuranosyl) Quinoline3Carboxylic Acid Inhibits HIV1 Replication by Targeting the Enzyme Reverse Transcriptase (original) (raw)
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Current HIV Research, 2009
We recently described that the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-( -Dribofuranosyl) quinoline-3-carboxylic acid (compound A) inhibits the human immunodeficiency virus type 1 (HIV-1) enzyme reverse transcriptase (RT), and its replication in primary cells. Based on these findings, we performed kinetic studies to investigate the mode of inhibition of compound A and its aglycan analog (compound B). We found that both molecules inhibited RT activity independently of the template/primer used. Nevertheless, compound A was 10-fold more potent than compound B. Compound A inhibited the RNA-dependent DNA polymerase (RDDP) activity of RT with an uncompetitive and a noncompetitive mode of action with respect to dTTP incorporation and to template/primer (TP) uptake, respectively. The kinetic pattern of the inhibition displayed by compound A was probably due to its greater affinity for the ternary complex (RT-TP-dNTP) than the enzyme alone or the binary complex (RT-TP). Besides, by means of molecular modeling, we show that compound A bound on the NNRTI binding pocket of RT. However, our molecule targets such a site by making novel interactions with the enzyme RT, when compared to NNRTIs. These include a hydrogen bridge between the 2'-OH of our compound and the Tyr675 of the enzyme RT's chain B. Therefore, compound A is able to synergize with both a NRTI (AZT-TP) and a NNRTI (efavirenz). Taken together, our results suggest that compound A displays a novel mechanism of action, which may be different from classical NRTIs and NNRTIs.
Current Hiv Research, 2009
We recently described that the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-( -Dribofuranosyl) quinoline-3-carboxylic acid (compound A) inhibits the human immunodeficiency virus type 1 (HIV-1) enzyme reverse transcriptase (RT), and its replication in primary cells. Based on these findings, we performed kinetic studies to investigate the mode of inhibition of compound A and its aglycan analog (compound B). We found that both molecules inhibited RT activity independently of the template/primer used. Nevertheless, compound A was 10-fold more potent than compound B. Compound A inhibited the RNA-dependent DNA polymerase (RDDP) activity of RT with an uncompetitive and a noncompetitive mode of action with respect to dTTP incorporation and to template/primer (TP) uptake, respectively. The kinetic pattern of the inhibition displayed by compound A was probably due to its greater affinity for the ternary complex (RT-TP-dNTP) than the enzyme alone or the binary complex (RT-TP). Besides, by means of molecular modeling, we show that compound A bound on the NNRTI binding pocket of RT. However, our molecule targets such a site by making novel interactions with the enzyme RT, when compared to NNRTIs. These include a hydrogen bridge between the 2'-OH of our compound and the Tyr675 of the enzyme RT's chain B. Therefore, compound A is able to synergize with both a NRTI (AZT-TP) and a NNRTI (efavirenz). Taken together, our results suggest that compound A displays a novel mechanism of action, which may be different from classical NRTIs and NNRTIs.
Current HIV research
We recently described that the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(beta-D-ribofuranosyl) quinoline-3-carboxylic acid (compound A) inhibits the human immunodeficiency virus type 1 (HIV-1) enzyme reverse transcriptase (RT), and its replication in primary cells. Based on these findings, we performed kinetic studies to investigate the mode of inhibition of compound A and its aglycan analog (compound B). We found that both molecules inhibited RT activity independently of the template/primer used. Nevertheless, compound A was 10-fold more potent than compound B. Compound A inhibited the RNA-dependent DNA polymerase (RDDP) activity of RT with an uncompetitive and a noncompetitive mode of action with respect to dTTP incorporation and to template/primer (TP) uptake, respectively. The kinetic pattern of the inhibition displayed by compound A was probably due to its greater affinity for the ternary complex (RT-TP-dNTP) than the enzyme alone or the binary complex (RT...
Promising novel compounds for the generation of new anti-HIV-RT therapeutic drugs
HIV Therapy, 2009
Molecules that target the allosteric site on reverse transcriptase n Etravirine and TMC278 are diarylpyrimidine derivatives that have displayed the best results against drug-resistant strains of HIV-1. n Etravirine is the latest non-nucleoside reverse transcriptase inhibitor (NNRTI) approved by US FDA for employment in HAART. n Resilience and small bulk volume of second generation NNRTIs are the main features of these drugs that overcome the loss of contact points, which occurs after resistance mutations. Molecules producing the same effect as NNRTIs but not docking at the classical allosteric site at the palm region of reverse transcriptase n Some NNRTI-associated mutations of reverse transcriptase (RT) do not occur in the NNRTI-binding site, but cause distortion to the side chains of Tyr residues important for nevirapine docking.
Proceedings of the National Academy of Sciences of the United States of America, 1996
The quinoxaline nonnucleoside RT inhibitor (NNRTI) (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4-dihydroquinoxaline-2(1H)-thione (HBY 097) was used to select for drug-resistant HIV-1 variants in vitro. The viruses first developed mutations affecting the NNRTIbinding pocket, and five of six strains displayed the RT G190-E substitution, which is characteristic for HIV-1 resistance against quinoxalines. In one variant, a new mutant (G190->Q) most likely evolved from preexisting G190->E mutants. The negative charge introduced by the G190->E substitution was maintained at that site of the pocket by simultaneous selection for V179-D together with G190-Q. After continued exposure to the drug, mutations at positions so far known to be specific for resistance against nucleoside RT inhibitors (NRTIs) (L74-*V/I and V75->L/I) were consistently detected in all cultures. The inhibitory activities of the cellular conversion product of 2',3'-dideoxyinosine (ddl, didanosine), 2',3'-dideoxyadenosine (ddA) and of 2',3'didehydro-3'-deoxythymidine (d4T, stavudine) against these late-passage viruses were shown to be enhanced with the
Antimicrobial Agents and Chemotherapy, 1992
The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is potently inhibited by a structurally diverse group of nonnucleoside compounds. These include pyridinone derivatives, tetrahydroimadazo[4,5,1-j,kJ[1,41-benzodiazepin-2(lH)-one and-thione, and BI-RG-587 (nevirapine). The compounds act noncompetitively, by an unknown mechanism, with respect to template-primer and nucleotide substrates. Despite a high degree of similarity between the 1IV-1 and HIV-2 RTs, the HIV-2 enzyme is totally insensitive to these inhibitors. Using a novel method for joining DNA sequences, we have exploited this difference between the two enzymes to identify the regions of the RT that contribute to the compounds' inhibitory activities. The relative in vitro sensitivities of HIV-1/HIV-2 chimeric and site-specific mutant enzymes were determined. Sensitivity to inhibition was largely, though not exclusively, dependent upon the RT region defined by amino acid residues 176 to 190, with specific contributions by residues 181 and 188. The region defined by residues 101 to 106 was found to functionaliy interact with the domain from 155 to 217. In addition, the functional equivalence of the three inhibitor groups was shown. Upon infection of susceptible cells by human immunodeficiency virus type 1 (HIV-1), the viral reverse transcriptase (RT) catalyzes the synthesis of a double-stranded DNA copy of the viral RNA genome. This reverse transcription is essential for viral infectivity, as inhibition of RT blocks viral replication. Thus, this enzyme has been a major focus in anti-HIV drug development and is the target of the nucleoside analogs 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI), which are the only currently approved drugs for anti-HIV therapy. These drugs appear to act by mediating premature chain termination of nascent DNA strands (reviewed in reference 17). Neither of these drugs is absolutely HIV specific, and treatment is associated with toxicity that limits their long-term use in the clinic. A separate pharmacologic class of nonnucleoside inhibitors was recently identified and consists of several distinct structural classes of compounds. These are shown in Fig. 1 and include L-697,639, a member of the pyridinone class of inhibitors (7, 23); BI-RG-587 (nevirapine), one of several inhibitory dipyridodiazepinones (16); and R82150 and R82913, tetrahydroimadazo[4,5,1-j,k][1,4]-benzodiazepin-2 (1H)-one and-thione (TIBO) compounds (19). Inhibition of RT activity by these compounds is characteristic of a slowly binding, reversible inhibitor and is noncompetitive with respect to template-primer and nucleotide substrates (6, 7, 16, 29, 30). In contrast to the nucleoside analogs, these compounds are highly specific for HIV-1 RT (RT1), and little or no inhibitory activity is observed against a variety of other viral or cellular polymerases, including the HIV-2 RT (RT2) (6, 7, 16, 29). A major concern in any antiviral drug development effort * Corresponding author.