Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We designed, synthesized, and identified UIC-94017 (TMC114), a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing a 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) and a sulfonamide isostere which is extremely potent against laboratory HIV-1 strains and primary clinical isolates (50% inhibitory concentration [IC(50)], approximately 0.003 micro M; IC(90), approximately 0.009 micro M) with minimal cytotoxicity (50% cytotoxic concentration for CD4(+) MT-2 cells, 74 micro M). UIC-94017 blocked the infectivity and replication of each of HIV-1(NL4-3) variants exposed to and selected for resistance to saquinavir, indinavir, nelfinavir, or ritonavir at concentrations up to 5 micro M (IC(50)s, 0.003 to 0.029 micro M), although it was less active against HIV-1(NL4-3) variants selected for resistance to amprenavir (IC(50), 0.22 micro M). UIC-94017 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents. Structural analyses revealed that the close contact of UIC-94017 with the main chains of the protease active-site amino acids (Asp-29 and Asp-30) is important for its potency and wide spectrum of activity against multi-PI-resistant HIV-1 variants. Considering the favorable pharmacokinetics of UIC-94017 when administered with ritonavir, the present data warrant that UIC-94017 be further developed as a potential therapeutic agent for the treatment of primary and multi-PI-resistant HIV-1 infections.
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PMID:Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro. 1450 19

TMC114, a newly designed human immunodeficiency virus type 1 (HIV-1) protease inhibitor, is extremely potent against both wild-type (wt) and multidrug-resistant (MDR) viruses in vitro as well as in vivo. Although chemically similar to amprenavir (APV), the potency of TMC114 is substantially greater. To examine the basis for this potency, we solved crystal structures of TMC114 complexed with wt HIV-1 protease and TMC114 and APV complexed with an MDR (L63P, V82T, and I84V) protease variant. In addition, we determined the corresponding binding thermodynamics by isothermal titration calorimetry. TMC114 binds approximately 2 orders of magnitude more tightly to the wt enzyme (K(d) = 4.5 x 10(-12) M) than APV (K(d) = 3.9 x 10(-10) M). Our X-ray data (resolution ranging from 2.2 to 1.2 A) reveal strong interactions between the bis-tetrahydrofuranyl urethane moiety of TMC114 and main-chain atoms of D29 and D30. These interactions appear largely responsible for TMC114's very favorable binding enthalpy to the wt protease (-12.1 kcal/mol). However, TMC114 binding to the MDR HIV-1 protease is reduced by a factor of 13.3, whereas the APV binding constant is reduced only by a factor of 5.1. However, even with the reduction in binding affinity to the MDR HIV protease, TMC114 still binds with an affinity that is more than 1.5 orders of magnitude tighter than the first-generation inhibitors. Both APV and TMC114 fit predominantly within the substrate envelope, a property that may be associated with decreased susceptibility to drug-resistant mutations relative to that of first-generation inhibitors. Overall, TMC114's potency against MDR viruses is likely a combination of its extremely high affinity and close fit within the substrate envelope.
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PMID:Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor. 1547 40

A capillary electrophoretic (CE) method was developed for the separation of diastereoisomers of a new human immunodeficiency virus (HIV) protease inhibitor TMC114. In total 16 isomers of this drug have been synthesized (eight pairs of enantiomers). We succeeded in the separation of the eight diastereoisomers, but no enantiomers could be separated. Because of the high similarity and water-insolubility of these isomers, the separation is a real challenge. Different CE modes were tried out: capillary zone electrophoresis (CZE), nonaqueous capillary electrophoresis (NACE), micellar electrokinetic capillary chromatography (MEKC), and microemulsion electrokinetic capillary chromatography (MEEKC). Only MEEKC offered resolution of these compounds.
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PMID:Development of a capillary electrophoretic method for the separation of diastereoisomers of a new human immunodeficiency virus protease inhibitor. 1569 Apr 35

The purpose of this study was to characterize the antiviral activity, cytotoxicity, and mechanism of action of TMC114, a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI). TMC114 exhibited potent anti-HIV activity with a 50% effective concentration (EC50) of 1 to 5 nM and a 90% effective concentration of 2.7 to 13 nM. TMC114 exhibited no cytotoxicity at concentrations up to 100 muM (selectivity index, >20,000). All viruses in a panel of 19 recombinant clinical isolates carrying multiple protease mutations and demonstrating resistance to an average of five other PIs, were susceptible to TMC114, defined as a fold change in EC50 of <4. TMC114 was also effective against the majority of 1,501 PI-resistant recombinant viruses derived from recent clinical samples, with EC50s of <10 nM for 75% of the samples. In sequential passage experiments using HIV-1 LAI, two mutations (R41T and K70E) were selected. One selected virus showed a 10-fold reduction in susceptibility to TMC114, but <10-fold reductions in susceptibility to the current PIs (atazanavir was not assessed), except saquinavir. However, when the selected mutations were introduced into a laboratory strain by site-directed mutagenesis, they had no effect on susceptibility to TMC114 or other PIs. There was no evidence of antagonism between TMC114 and any currently available PIs or reverse transcriptase inhibitors. Combinations with ritonavir, nelfinavir, and amprenavir showed some evidence of synergy. These results suggest that TMC114 is a potential candidate for the treatment of both naive and PI-experienced patients with HIV.
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PMID:TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. 1591 27

Human immunodeficiency virus (HIV) infection affects close to 40 million individuals worldwide. Since 1981 when the first case reports of individuals dying from a then rare opportunistic infection were published, twenty million people have died from this epidemic. With 3 or more antiretrovirals as the standard of care, the prevalence of single, double and triple-class resistant HIV strains has increased significantly over the last 5 years due to the tremendous replicative capacity of HIV and selective drug pressure. With greater resistance comes the need for novel and effective antiretrovirals to treat these resistant strains. The purpose of this review is to highlight the most promising agents and classes in Phase II-III drug development by assessing the clinical efficacy, pharmacology, resistance and tolerability. Three out of the four existing antiretroviral classes (nucleosides, non-nucleosides, protease inhibitors) with agents in clinical trials will be discussed such as nucleoside reverse transcriptase inhibitors (D-d4FC, SPD754), non-nucleoside reverse transcriptase inhibitors (capravirine, TMC125) and protease inhibitors (tipranavir, TMC114). In the next several years, antiretrovirals from novel pharmacologic classes will enter the HIV armamentarium. Based on the early clinical studies, these promising agents will be reviewed from the following classes: attachment inhibitors (TNX-355, BMS-488043), CCR5 coreceptor antagonists (SCH-D, UK-427857, GW 873140) and a maturation inhibitor (PA-457). It is hoped that these agents will represent a therapeutic advance and better activity against HIV resistant strains by providing effective therapy that will reduce viral load, increase the CD4+ cell count and ultimately, prolong survival with minimal adverse effects.
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PMID:On the horizon: promising investigational antiretroviral agents. 1651 88

Darunavir (DRV; TMC114; Prezista) is a human immunodeficiency virus (HIV) protease inhibitor used in combination with low-dose ritonavir (RTV) (DRV/r) as a pharmacokinetic enhancer. Protease inhibitor absorption may be decreased during coadministration of drugs that limit stomach acid secretion and increase gastric pH. This study was conducted to investigate the effect of ranitidine and omeprazole on the plasma pharmacokinetics of DRV and RTV in HIV-negative healthy volunteers. Sixteen volunteers completed the study and received DRV/r, DRV/r plus ranitidine, and DRV/r plus omeprazole, in three separate sessions. Treatment was given for 4 days with an additional morning dose on day 5, and regimens were separated by a washout period of 7 days. Samples were taken over a 12-h period on day 5 for the assessment of DRV and RTV plasma concentrations. Pharmacokinetic parameters assessed included DRV area under the curve, maximum plasma concentration, and trough plasma concentration. The least-squares mean ratios and 90% confidence intervals are reported with treatment of DRV/r alone as a reference. Compared with DRV/r alone, no significant changes in DRV pharmacokinetic parameters were observed during coadministration of DRV/r and either ranitidine or omeprazole. Treatment regimens were generally well tolerated, and no serious adverse events were reported. In conclusion, coadministration of DRV/r and ranitidine or omeprazole was well tolerated by the volunteers. Ranitidine and omeprazole did not have a significant influence on DRV pharmacokinetics. No dose adjustments are required when DRV/r is coadministered with omeprazole or ranitidine.
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PMID:Pharmacokinetic interaction between darunavir boosted with ritonavir and omeprazole or ranitidine in human immunodeficiency virus-negative healthy volunteers. 1721 Jul 68

The high incidence of cross-resistance between human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) limits their sequential use. This necessitates the development of PIs with a high genetic barrier and a broad spectrum of activity against PI-resistant HIV, such as tipranavir and darunavir (TMC114). We performed a surface plasmon resonance-based kinetic study to investigate the impact of PI resistance-associated mutations on the protease binding of five PIs used clinically: amprenavir, atazanavir, darunavir, lopinavir, and tipranavir. With wild-type protease, the binding affinity of darunavir was more than 100-fold higher than with the other PIs, due to a very slow dissociation rate. Consequently, the dissociative half-life of darunavir was much higher (>240 h) than that of the other PIs, including darunavir's structural analogue amprenavir. The influence of protease mutations on the binding kinetics was tested with five multidrug-resistant (MDR) proteases derived from clinical isolates harboring 10 to 14 PI resistance-associated mutations with a decreased susceptibility to various PIs. In general, all PIs bound to the MDR proteases with lower binding affinities, caused mainly by a faster dissociation rate. For amprenavir, atazanavir, lopinavir, and tipranavir, the decrease in affinity with MDR proteases resulted in reduced antiviral activity. For darunavir, however, a nearly 1,000-fold decrease in binding affinity did not translate into a weaker antiviral activity; a further decrease in affinity was required for the reduced antiviral effect. These observations provide a mechanistic explanation for darunavir's potent antiviral activity and high genetic barrier to the development of resistance.
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PMID:Binding kinetics of darunavir to human immunodeficiency virus type 1 protease explain the potent antiviral activity and high genetic barrier. 1792 44