Tomokazu Yoshinaga

Shionogi & Co., Ltd., Ōsaka, Ōsaka, Japan

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Publications (23)82.76 Total impact

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    ABSTRACT: Influenza virus infection increases susceptibility to bacterial infection and mortality in humans. Although the efficacy of approved intravenous peramivir, a neuraminidase (NA) inhibitor, against influenza virus infection has been reported, its efficacy against bacterial co-infection, which occurs during the period of viral shedding, was not fully investigated. To further understand the significance of treatment with peramivir, we assessed the efficacy of peramivir against a bacterial co-infection model in mice caused by clinically isolated influenza A(H1N1)pdm09 virus and Streptococcus pneumoniae. Mice were infected with influenza A(H1N1)pdm09. Peramivir was intravenously administered after the viral infection. At 2days post viral infection, the mice were infected with S. pneumoniae. Peramivir efficacy was measured by the survival rates and viral titers, bacterial titers, or proinflammatory cytokine concentrations in lung homogenates. Peramivir treatment reduced the mortality of mice infected with influenza virus and S. pneumoniae. The survival rate in the peramivir-treated group was significantly higher than that in the oseltamivir-treated group. Viral titers and proinflammatory cytokine responses in the peramivir-treated group were significantly lower than those in the oseltamivir-treated group until at 2days post viral infection. Bacterial titer was significantly lower in the peramivir-treated group than in the oseltamivir-treated group at 4days post viral infection. These results demonstrated that peramivir inhibits viral replication, consequently leading to bacterial clearance and prevention of mortality during severe murine bacterial co-infection, which occurs during the period of viral shedding, with the efficacy of peramivir being superior to that of oseltamivir. Copyright © 2015. Published by Elsevier B.V.
    Antiviral Research 03/2015; 117. DOI:10.1016/j.antiviral.2015.02.012 · 3.43 Impact Factor
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    ABSTRACT: The recently approved HIV-1 integrase strand transfer inhibitor (INSTI) dolutegravir (DTG, S/GSK1349572) has overall advantageous activity when tested in vitro against HIV-1 with raltegravir (RAL)- and elvitegravir (EVG)-resistant signature mutations. We conducted an in vitro resistance selection study using wild-type HIV-1 and mutants with E92Q, Y143C, Y143R, Q148H, Q148K, Q148R or N155H substitutions to assess the DTG in vitro barrier to resistance. No viral replication was observed at ≥ 32 nM DTG, whereas viral replication was observed at 160 nM RAL or EVG in mutants. In the Q148H/K/R mutants, secondary mutations encoding G140S/Q148H, E138K/Q148K, E138K/Q148R, and G140S/Q148R were identified with each INSTI and showed high resistance to RAL or EVG but limited resistance to DTG. E138K or G140S, as a secondary substitution to Q148H/K/R, was associated with partial recovery in viral infectivity and/or INSTI resistance. In E92Q, Y143C/R or N155H mutants, no secondary substitutions were associated with DTG. These in vitro results suggest that DTG has a high barrier to development of resistance in the presence of RAL or EVG signature mutations other than Q148. One explanation for this high barrier to resistance is that no additional secondary substitution to E92Q, Y143C, Y143R or N155H could simultaneously increase fold change in EC50 to DTG and infectivity. Although increased DTG resistance via the Q148 pathway and secondary substitutions occurs at low concentrations, a higher starting concentration may reduce or eliminate development of DTG resistance in this pathway in vitro. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Antimicrobial Agents and Chemotherapy 02/2015; 59(5). DOI:10.1128/AAC.04844-14 · 4.45 Impact Factor
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    ABSTRACT: GSK1265744 is a new HIV integrase strand transfer inhibitor (INSTI) engineered to deliver efficient antiviral activity with a once-daily, low-milligram dose that does not require a pharmacokinetic booster. The in vitro antiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or sub-nanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC50) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC50 relative to the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant signature mutants Y143R, Q148K, N155H, and G140S/Q148H (FC less than 6.1), while these mutants had a high FC to RAL (11 - >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen. These findings demonstrate that, similar to dolutegravir, GSK1265744 is differentiated as a new INSTI, having a markedly distinct resistance profile compared with earlier generation INSTIs, RAL and elvitegravir (EVG). The collective dataset supports further clinical development of GSK1265744.
    Antimicrobial Agents and Chemotherapy 11/2014; 59(1). DOI:10.1128/AAC.03909-14 · 4.45 Impact Factor
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    ABSTRACT: Signature HIV-1 integrase mutations associated with clinical raltegravir resistance involve 1 of 3 primary genetic pathways, Y143C/R, Q148H/K/R and N155H, the latter 2 of which confer cross-resistance to elvitegravir. In accord with clinical findings, in vitro drug resistance profiling studies with wild-type and site-directed integrase mutant viruses have shown significant fold increases in raltegravir and elvitegravir resistance for the specified viral mutants relative to wild-type HIV-1. Dolutegravir, in contrast, has demonstrated clinical efficacy in subjects failing raltegravir therapy due to integrase mutations at Y143, Q148 or N155, which is consistent with its distinct in vitro resistance profile as dolutegravir's antiviral activity against these viral mutants is equivalent to its activity against wild-type HIV-1. Kinetic studies of inhibitor dissociation from wild-type and mutant integrase-viral DNA complexes have shown that dolutegravir also has a distinct off-rate profile with dissociative half-lives substantially longer than those of raltegravir and elvitegravir, suggesting that dolutegravir's prolonged binding may be an important contributing factor to its distinct resistance profile. To provide a structural rationale for these observations, we constructed several molecular models of wild-type and clinically relevant mutant HIV-1 integrase enzymes in complex with viral DNA and dolutegravir, raltegravir or elvitegravir. Here, we discuss our structural models and the posited effects that the integrase mutations and the structural and electronic properties of the integrase inhibitors may have on the catalytic pocket and inhibitor binding and, consequently, on antiviral potency in vitro and in the clinic.
    PLoS ONE 10/2013; 8(10):e77448. DOI:10.1371/journal.pone.0077448 · 3.53 Impact Factor
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    ABSTRACT: We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.
    Journal of Medicinal Chemistry 07/2013; 56(14). DOI:10.1021/jm400645w · 5.48 Impact Factor
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    ABSTRACT: This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone HIV-1 integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of bicyclic carbamoyl pyridone analogs to address conformational issues from our initial SAR studies. This modification of the core unit succeeded to deliver low nM potency in standard antiviral assays. An additional hydroxyl substituent on the bicyclic scaffold provides remarkable improvement of antiviral efficacies against clinically relevant resistant viruses. These findings led to additional cyclic tethering of the naked hydroxyl group resulting tricyclic carbamoyl pyridone inhibitors to address remaining issues and deliver potential clinical candidates. The tricyclic carbamoyl pyridone derivatives described herein served as the immediate lead in molecules to the next generation integrase inhibitor dolutegravir which is currently in late stage clinical evaluation.
    Journal of Medicinal Chemistry 01/2013; 56(3). DOI:10.1021/jm301550c · 5.48 Impact Factor
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    ABSTRACT: Background: HIV-1 integrase is a virally encoded enzyme essential for lentiviral replication. Assiduous medicinal chemistry efforts culminated in the discovery of raltegravir, the first marketed HIV-1 integrase inhibitor (INI). However, there is significant opportunity for improvement including overall dose burden, dosing interval and potency against resistant viruses. Our molecular design approach used a two-metal binding pharmacophore strategy and succeeded in identification of carbamoyl pyridone HIV-1 INIs. This enriched core scaffold has abundant structural features expanding the opportunity to control drug properties, leading to the discovery of S/GSK1265744. Methods: The carbamoyl pyridone scaffold was derivatized and evaluated for antiviral activity against wild-type virus (±HSA) along with key INI-resistant mutants. Animal pharmacokinetic profiles including a key measure of the trough drug concentration over protein-adjusted antiviral potency (C24/PAIC50) along with in vitro DMPK properties, were used along with the virological data for compound selection. Results: The carbamoyl pyridone series inhibitors exhibited potent antiviral profiles with promising DMPK properties. S/GSK1265744 demonstrated good coverage of C24 over PAIC50 predicting low mg unboosted once daily dosing, now validated in phase 2 clinical studies. These preclinical data along with a long human T1/2 of ~30 hours in oral tablet study supports S/GSK1265744 as a long acting parenteral agent for once-monthly or less frequent dosing. Conclusions: A medicinal chemistry approach utilizing key viral mutants in combination with C24/PAIC50 has allowed for discovery of S/GSK1265744. This agent is currently in phase 2 development evaluating a novel, long-acting parenteral route of administration and may enable new approaches to HIV therapy and prevention.
    Journal of the International AIDS Society 11/2012; 15(6):18267. DOI:10.7448/IAS.15.6.18267 · 4.21 Impact Factor
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    ABSTRACT: Our group has focused on expanding the scope of a two-metal binding pharmacophore concept to explore HIV-1 integrase inhibitors through medicinal chemistry efforts to design novel scaffolds which allow for improvement of pharmacokinetic (PK) and resistance profiles. A novel chelating scaffold was rationally designed to effectively coordinate two magnesium cofactors and to extend an aromatic group into an optimal hydrophobic pharmacophore space. The new chemotype, consisting of a carbamoyl pyridone core unit, shows high inhibitory potency in both enzymatic and antiviral assay formats with low nM IC(50) and encouraging potency shift effects in the presence of relevant serum proteins. The new inhibitor design displayed a remarkable PK profile suggestive of once daily dosing without the need for a PK booster as demonstrated by robust drug concentrations at 24 h after oral dosing in rats, dogs, and cynomolgus monkeys.
    Journal of Medicinal Chemistry 09/2012; 55(20):8735-44. DOI:10.1021/jm3010459 · 5.48 Impact Factor
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    ABSTRACT: A potent inhibitor for Vibrio cholerae neuraminidase (VCNA) was developed by using a novel two-step strategy, a target amino acid validation using mechanism-based labeling information, and a potent inhibitor search using a focused library. The labeling information suggested the hidden dynamics of a loop structure of VCNA, which can be a potential target of the novel inhibitor. A focused library composed of 187 compounds was prepared from a 9-azide derivative of 2,3-dehydro-N-acetylneuraminic acid (DANA) to interrupt the function of the loop of the labeled residues. Inhibitor 3 c showed potent inhibition properties and was the strongest inhibitor with FANA, a N-trifluoroacetyl derivative of DANA. Validation studies of the inhibitor with a detergent and a Lineweaver-Burk plot suggested that the 9-substitution group would interact hydrophobically with the target loop moiety, adding a noncompetitive inhibition property to the DANA skeleton. This information enabled us to design compound 4 having the combined structure of 3 c and FANA. Compound 4 showed the most potent inhibition (K(i) =73 nM, mixed inhibition) of VCNA with high selectivity among the tested viral, bacterial, and mammal neuraminidases.
    Chemistry - An Asian Journal 04/2011; 6(4):1048-56. DOI:10.1002/asia.201000594 · 3.94 Impact Factor
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    ABSTRACT: S/GSK1349572 is a next-generation HIV integrase (IN) inhibitor designed to deliver potent antiviral activity with a low-milligram once-daily dose requiring no pharmacokinetic (PK) booster. In addition, S/GSK1349572 demonstrates activity against clinically relevant IN mutant viruses and has potential for a high genetic barrier to resistance. S/GSK1349572 is a two-metal-binding HIV integrase strand transfer inhibitor whose mechanism of action was established through in vitro integrase enzyme assays, resistance passage experiments, activity against viral strains resistant to other classes of anti-HIV agents, and mechanistic cellular assays. In a variety of cellular antiviral assays, S/GSK1349572 inhibited HIV replication with low-nanomolar or subnanomolar potency and with a selectivity index of 9,400. The protein-adjusted half-maximal effective concentration (PA-EC(50)) extrapolated to 100% human serum was 38 nM. When virus was passaged in the presence of S/GSK1349572, highly resistant mutants were not selected, but mutations that effected a low fold change (FC) in the EC(50) (up to 4.1 fold) were identified in the vicinity of the integrase active site. S/GSK1349572 demonstrated activity against site-directed molecular clones containing the raltegravir-resistant signature mutations Y143R, Q148K, N155H, and G140S/Q148H (FCs, 1.4, 1.1, 1.2, and 2.6, respectively), while these mutants led to a high FC in the EC(50) of raltegravir (11- to >130-fold). Either additive or synergistic effects were observed when S/GSK1349572 was tested in combination with representative approved antiretroviral agents; no antagonistic effects were seen. These findings demonstrate that S/GSK1349572 would be classified as a next-generation drug in the integrase inhibitor class, with a resistance profile markedly different from that of first-generation integrase inhibitors.
    Antimicrobial Agents and Chemotherapy 02/2011; 55(2):813-21. DOI:10.1128/AAC.01209-10 · 4.45 Impact Factor
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    ABSTRACT: The medicinal chemistry and structure-activity relationships for a novel series of 7-benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV-integrase inhibitors are disclosed. Substituent effects were evaluated at the N-1, C-3, and 7-benzyl positions of the naphthyridinone ring system. Low nanomolar IC(50) values were achieved in an HIV-integrase strand transfer assay with both carboxylic ester and carboxamide groups at C-3. More importantly, several carboxamide congeners showed potent antiviral activity in cellular assays. A 7-benzyl substituent was found to be critical for potent enzyme inhibition, and an N-(2-methoxyethyl)carboxamide moiety at C-3 significantly reduced plasma protein binding effects in vitro. Pharmacokinetic data in rats for one carboxamide analogue demonstrated oral bioavailability and reasonable in vivo clearance.
    Journal of Medicinal Chemistry 05/2009; 52(9):2754-61. DOI:10.1021/jm801404b · 5.48 Impact Factor
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    ABSTRACT: Passage of HIV-1 in the presence of integrase inhibitors (INIs) generates resistant viruses that have mutations in the integrase region. Integrase-resistant mutations Q148K and Q148R were identified as primary mutations with the passage of HIV-1 IIIB in the presence of INIs S-1360 or S/GSK-364735, respectively. Secondary amino acid substitutions E138K or G140S were observed when passage with INI was continued. The role of these mutations was investigated with molecular clones. Relative to Q148K alone, Q148K/E138K had 2- and >6-fold increases in resistance to S-1360 and S/GSK-364735, respectively, and the double mutant had slightly better infectivity and replication kinetics. In contrast, Q148K/G140S and Q148R/E138K had nearly equivalent or slightly reduced fold resistance to the INI compared with their respective Q148 primary mutants, and had increases in infectivity and replication kinetics. Recovery of these surrogates of viral fitness coincided with the recovery of integration efficiency of viral DNA into the host cell chromosome for these double mutants. These data show that recovery of viral integration efficiency can be an important factor for the emergence and maintenance of INI-resistant mutations.
    Antiviral research 12/2008; 81(2):141-6. DOI:10.1016/j.antiviral.2008.10.007 · 3.43 Impact Factor
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    ABSTRACT: Resistance passage studies were conducted with five INIs (integrase inhibitors) that have been tested in clinical trials to date: a new naphthyridinone-type INI S/GSK-364735, raltegravir, elvitegravir, L-870,810 and S-1360. In establishing the passage system and starting from concentrations several fold above the EC(50) value, resistance mutations against S-1360 and related diketoacid-type compounds could be isolated from infected MT-2 cell cultures from day 14 to 28. Q148R and F121Y were the two main pathways of resistance to S/GSK-364735. Q148R/K and N155H, which were found in patients failing raltegravir treatment in Phase IIb studies, were observed during passage with raltegravir with this method. The fold resistance of 40 mutant molecular clones versus wild type virus was compared with these five INIs. The overall resistance pattern of S/GSK-364735 was similar to that of raltegravir and other INIs. However, different fold resistances of particular mutations were noted among different INIs, reflecting a potential to develop INIs with distinctly different resistant profiles.
    Antiviral research 08/2008; 80(2):213-22. DOI:10.1016/j.antiviral.2008.06.012 · 3.43 Impact Factor
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    ABSTRACT: The naphthyridinone GSK364735 potently inhibited recombinant human immunodeficiency virus type 1 (HIV-1) integrase in a strand transfer assay (mean 50% inhibitory concentration +/- standard deviation, 8 +/- 2 nM). As expected based on the structure of the drug, it bound competitively with another two-metal binding inhibitor (Kd [binding constant], 6 +/- 4 nM). In a number of different cellular assays, GSK364735 inhibited HIV replication with potency at nanomolar concentrations (e.g., in peripheral blood mononuclear cells and MT-4 cells, 50% effective concentrations were 1.2 +/- 0.4 and 5 +/- 1 nM, respectively), with selectivity indexes of antiviral activity versus in-assay cytotoxicity of at least 2,200. When human serum was added, the antiviral potency decreased (e.g., a 35-fold decrease in the presence of 100% human serum was calculated by extrapolation from the results of the MT-4 cell assay). In cellular assays, GSK364735 blocked viral DNA integration, with a concomitant increase in two-long-terminal-repeat circles. As expected, this integrase inhibitor was equally active against wild-type viruses and mutant viruses resistant to approved drugs targeting either reverse transcriptase or protease. In contrast, some but not all viruses resistant to other integrase inhibitors were resistant to GSK364735. When virus was passaged in the presence of the inhibitor, we identified resistance mutations within the integrase active site that were the same as or similar to mutations arising in response to other two-metal binding inhibitors. Finally, either additive or synergistic effects were observed when GSK364735 was tested in combination with approved antiretrovirals (i.e., no antagonistic effects were seen). Thus, based on all the data, GSK364735 exerted potent antiviral activity through the inhibition of viral DNA integration by interacting at the two-metal binding site within the catalytic center of HIV integrase.
    Antimicrobial Agents and Chemotherapy 04/2008; 52(3):901-8. DOI:10.1128/AAC.01218-07 · 4.45 Impact Factor
  • ChemInform 11/2007; 38(47). DOI:10.1002/chin.200747115
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    ABSTRACT: The two-metal binding model we previously reported as an inhibition mechanism of HIV integrase (HIV IN) produced a new direction in modification of 2-hydroxy-3-heteroaryl acrylic acid inhibitors (HHAAs). Here we present a novel series of HIV IN inhibitors having a 3-hydroxy-1,5-dihydro-pyrrol-2-one moiety (HDPO) as an advanced analog of HHAAs. This cyclic modification of the chelating region of HHAA produces a favorable configuration to coordinate two-metal ions in HIV IN, which consequently gave improvements in not only enzymatic assay but also antiviral cell based assay in many cases.
    Bioorganic & Medicinal Chemistry 09/2007; 15(16):5487-92. DOI:10.1016/j.bmc.2007.05.052 · 2.95 Impact Factor
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    ABSTRACT: We present a novel series of HIV integrase inhibitors, showing IC(50)s ranging from 0.01 to over 370microM in an enzymatic assay. Furthermore, pharmacophore modeling study for the inhibitors was carried out to elucidate the structure-activity relationships. Finally, we found a 3D-pharmacophore model, which is composed of a hydrophilic and a hydrophobic domain, providing valuable information for designing other novel types of integrase inhibitors.
    Bioorganic & Medicinal Chemistry 01/2007; 14(24):8430-45. DOI:10.1016/j.bmc.2006.08.044 · 2.95 Impact Factor
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    ABSTRACT: We propose a two-metal binding model as a potential mechanism of chelating inhibitors against HIV integrase (HIV IN) represented by 2-hydroxy-3-heteroaryl acrylic acids (HHAAs). Potential inhibitors would bind to two metal ions in the active site of HIV IN to prevent human DNA from undergoing the integration reaction. Correlation of the results of metal (Mg(2+) and Mn(2+)) titration studies with HIV IN inhibition for a series of active and inactive compounds provides support for the model. Results suggest Mg(2+) is an essential cofactor for chelating inhibitors.
    Bioorganic & Medicinal Chemistry 01/2007; 14(24):8420-9. DOI:10.1016/j.bmc.2006.08.043 · 2.95 Impact Factor
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    ABSTRACT: For the purpose of discovering anti-HIV-1 agents from natural sources, water and EtOH extracts of 50 Thai plants were screened for their inhibitory activity against HIV-1 integrase (IN), an enzyme essential for viral replication. Of these plants, an EtOH extract of Coleus parvifolius Benth. (aerial parts) showed potent activity against HIV-1 IN with an IC50 value of 9.2 microg/mL. From this extract, 11 compounds were isolated and identified as luteolin 5-O-beta-d-glucopyranoside (1), luteolin (2), luteolin 7-methyl ether (3), luteolin 5-O-beta-d-glucuronide (4), 5-O-beta-d-glucopyranosyl-luteolin 7-methyl ether (5), rosmarinic acid (6), rosmarinic acid methyl ester (7), daucosterol (8), a mixture of alpha- and beta-amyrin (9, 10) and phytol (11). Of these compounds, rosmarinic acid methyl ester (7), rosmarinic acid (6), luteolin (2) and luteolin 7-methyl ether (3) exhibited inhibitory activities against HIV-1 IN with IC50 values of 3.1, 5.0, 11.0 and 11.0 microM, respectively. Among rosmarinic acid derivatives, the HIV-1 IN inhibitory activity increased in turn for a dimer (IC50 = 5.0 microM), a trimer (IC50 = 1.4 microM), and a tetramer (IC50 = 1.0 microM).
    Phytotherapy Research 03/2003; 17(3):232-9. DOI:10.1002/ptr.1111 · 2.40 Impact Factor
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    ABSTRACT: HIV integrase, the enzyme that inserts the viral DNA into the host chromosome, has no mammalian counterpart, making it an attractive target for antiviral drug design. As one of the three enzymes produced by HIV, it can be expected that inhibitors of this enzyme will complement the therapeutic use of HIV protease and reverse transcriptase inhibitors. We have determined the structure of a complex of the HIV-1 integrase core domain with a novel inhibitor, 5ClTEP, 1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)-pro penone, to 2.1-A resolution. The inhibitor binds centrally in the active site of the integrase and makes a number of close contacts with the protein. Only minor changes in the protein accompany inhibitor binding. This inhibitor complex will provide a platform for structure-based design of an additional class of inhibitors for antiviral therapy.
    Proceedings of the National Academy of Sciences 12/1999; 96(23):13040-3. DOI:10.1073/pnas.96.23.13040 · 9.81 Impact Factor