Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.16 (HIV-1 protease)
 2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The secreted aspartyl proteinase (Sap) of Candida albicans, which is believed to represent an important virulence factor of this opportunistic yeast, and the human immunodeficiency virus type 1 (HIV-1) protease, which is obligatory for the production of infectious virions, both belong to the same family of aspartyl proteinases. We have previously shown that the HIV-1 protease inhibitor Indinavir directly inhibits secretion and proteinase activity of Sap in a dose-dependent manner. Furthermore, at very high concentrations, viability of C. albicans is markedly reduced by Indinavir, indicating that HIV-1 protease inhibitors may possess antifungal activity. We thus proposed that these drugs may add to the resolution of mucosal candidiasis in HIV-1 infected subjects. We have now compared three different HIV-1 protease inhibitors. The rank order of Sap inhibition, already significant at 0.1 mg/ml for all protease inhibitors, was Ritonavir > Indinavir > Saquinavir. However, the cross-reactivity of Ritonavir to pepsin was also more pronounced compared with the other two. Indinavir did not affect Candida viability at concentrations up to 1 mg/ml, in line with our previous study. In contrast, at this concentration Saquinavir was even fungicidal as assessed by three different viability assays (colony formation assay, MTT assay, propidium iodide staining) whereas Ritonavir significantly affected the mitochondrial activity only (MTT assay). No influence on Candida viability was observed for any of the three at concentrations of 0.1 mg/ml or lower. It remains to be examined whether HIV-1 protease inhibitors or derivatives thereof may be suitable for in vivo therapy of subjects suffering from mucosal candidiasis resistant to current antimycotics.
Immunobiology 1999 Sep
PMID:Dissimilar attenuation of Candida albicans virulence properties by human immunodeficiency virus type 1 protease inhibitors. 1053 86

Nelfinavir is a potent inhibitor of the HIV-1 protease, which shows good inhibitory activity against HIV-1 in vitro. Initial clinical trials have shown that it has excellent activity in vivo in HIV-infected patients. The combination of 750 mg nelfinavir three times daily with zidovudine and lamivudine has been shown to cause a median reduction in HIV plasma RNA of approximately 2 log10 copies/ml, and to reduce plasma levels of RNA below the limit of detection (< 400 copies/ml) in 50-75% of patients after 12 months of treatment. This combination was associated with a mean increase of almost 200 CD4+ lymphocytes per mm3 at 12 months of therapy. The drug is well-tolerated, with mild diarrhea, which occurs in 12-20% of patients, being the most common side-effect. The pattern of initial protease mutations associated with nelfinavir resistance appears to be different from that seen with resistance to the other protease inhibitors, with the predominant initial mutation occurring at codon 30 of the HIV protease gene. Thus, initial trials indicate that nelfinavir is equivalent to other potent protease inhibitors and can be considered as a component in first-line combination therapy for HIV-infected patients.
AIDS 1999 Sep
PMID:Nelfinavir, a new protease inhibitor: early clinical results. 1054 84

The choice of initial antiretroviral regimen for treating people infected with HIV is crucial to successful long-term control of virus replication. Potent antiretroviral therapy substantially suppresses viral replication as measured by plasma HIV RNA levels to below limits of detection: the current standard of care is usually a combination of at least three drugs and frequently includes a protease inhibitor, or alternatively a non-nucleoside reverse transcriptase inhibitor (nnRTI). Patients who have low CD4+ cell counts (< or = 200 CD4+ cells/mm3) or high plasma HIV RNA levels (> or = 100,000 copies/ml) may not attain maximal suppression of HIV replication when treated with current regimens and may require more aggressive therapy. In contrast, patients with relatively normal CD4+ cell counts and low to non-measurable levels of plasma HIV RNA over prolonged periods (i.e., slow or non-progressors) may not require immediate antiretroviral therapy. These individuals should reconsider treatment when either the CD4+ cell count declines or the HIV RNA level increases. Early and potent antiretroviral therapy should provide more durable virological and clinical benefits for many patients, especially if they receive sufficient counselling and support to aid adherence to the treatment regimen. The optimum time to initiate antiretroviral therapy is not well established, but to maximise the recovery of the immune system and the virological and clinical benefits, initiation of therapy is generally recommended for individuals who have symptoms or those with plasma HIV RNA levels > 5000-10,000 copies/ml, or CD4+ cell counts < 500 cells/mm3. The current choice of initial antiretroviral regimens includes two nucleoside reverse transcriptase inhibitors (nRTI) with a potent, well-tolerated HIV-1 protease inhibitor or nnRTI. Recent short-term activity data (24-week comparative clinical trial data) indicate that regimens combining three nRTI, including abacavir, could also be considered. Other emerging combination regimens for consideration include two HIV-1 protease inhibitors with one or two nRTI, or a combination of drugs from all current categories (e.g., nRTI with a nnRTI and HIV-1 protease inhibitor). The goal of antiretroviral therapy is to maximise suppression of HIV replication and thereby prevent or delay viral resistance, restore immunological function and improve clinical outcome. Since evolution of the virus towards resistance can occur with plasma HIV RNA levels between 50 and 500 copies/ml, current standards for best suppression of HIV replication have shifted to declines in plasma HIV RNA to < 50 copies/ml. In addition, non-adherence to any regimen is associated with the greatest risk for virological failure. Therefore, both the decision to initiate therapy and the choice of initial therapy should be carefully weighted and balanced with the long-term implications of antiretroviral therapy.
AIDS 1999 Sep
PMID:Antiretroviral therapy in 1999 for antiretroviral-naive individuals with HIV infection. 1054 85

The extent to which human immunodeficiency virus (HIV) type 1 drug resistance compromises therapeutic efficacy is intimately tied to drug potency and exposure. Most HIV-1 protease inhibitors maintain in vivo trough levels above their human serum protein binding-corrected IC(95) values for wild-type HIV-1. However, these troughs are well below corrected IC(95) values for protease inhibitor-resistant viruses from patients experiencing virologic failure of indinavir and/or nelfinavir. This suggests that none of the single protease inhibitors would be effective after many cases of protease inhibitor failure. However, saquinavir, amprenavir, and indinavir blood levels are increased substantially when each is coadministered with ritonavir, with 12-h troughs exceeding corrected wild-type IC(95) by 2-, 7-, and 28-79-fold, respectively. These indinavir and amprenavir troughs exceed IC(95) for most protease inhibitor-resistant viruses tested. This suggests that twice-daily indinavir-ritonavir and, to a lesser extent, amprenavir-ritonavir may be effective for many patients with viruses resistant to protease inhibitors.
J Infect Dis 2000 Sep
PMID:Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. 1123 20

Better understanding of the mechanisms of proinflammatory cytokine production during human immunodeficiency virus (HIV) type 1 infection is of pivotal importance. The effect of HIV-1 infection on recombinant CD40 ligand (CD40L)-induced interleukin (IL)-1beta and IL-6 production by human macrophages was analyzed. ELISA and cytofluorometric analysis demonstrated that CD40L stimulation of HIV-1-infected macrophages resulted in substantial production of IL-1beta and IL-6. In contrast, no cytokine response was observed in uninfected cells. No modulation of the receptor for CD40 was found to account for the enhanced response to CD40L. The CD40L effect was not due to lipopolysaccharide contamination and was completely abrogated by preincubation with a monoclonal anti-CD40L antibody. mRNA studies indicated that the priming effect of HIV-1 on the macrophage response to CD40L was regulated at the transcriptional level. Finally, the effect of HIV-1 on the cytokine response could not be abolished by the HIV-1 protease inhibitor U75875 at concentrations that completely suppressed HIV-1 replication.
J Infect Dis 2000 Sep
PMID:Human immunodeficiency virus type 1 infection modulates the interleukin (IL)-1beta and IL-6 responses of human macrophages to CD40 ligand stimulation. 1095 Jul 71

BMS-232632 is an azapeptide human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor that displays potent anti-HIV-1 activity (50% effective concentration [EC(50)], 2.6 to 5.3 nM; EC(90), 9 to 15 nM). In vitro passage of HIV-1 RF in the presence of inhibitors showed that BMS-232632 selected for resistant variants more slowly than nelfinavir or ritonavir did. Genotypic and phenotypic analysis of three different HIV strains resistant to BMS-232632 indicated that an N88S substitution in the viral protease appeared first during the selection process in two of the three strains. An I84V change appeared to be an important substitution in the third strain used. Mutations were also observed at the protease cleavage sites following drug selection. The evolution to resistance seemed distinct for each of the three strains used, suggesting multiple pathways to resistance and the importance of the viral genetic background. A cross-resistance study involving five other protease inhibitors indicated that BMS-232632-resistant virus remained sensitive to saquinavir, while it showed various levels (0. 1- to 71-fold decrease in sensitivity)-of cross-resistance to nelfinavir, indinavir, ritonavir, and amprenavir. In reciprocal experiments, the BMS-232632 susceptibility of HIV-1 variants selected in the presence of each of the other HIV-1 protease inhibitors showed that the nelfinavir-, saquinavir-, and amprenavir-resistant strains of HIV-1 remained sensitive to BMS-232632, while indinavir- and ritonavir-resistant viruses displayed six- to ninefold changes in BMS-232632 sensitivity. Taken together, our data suggest that BMS-232632 may be a valuable protease inhibitor for use in combination therapy.
Antimicrob Agents Chemother 2000 Sep
PMID:In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632. 1095 74

Human immunodeficiency virus type 1 (HIV-1) resistance to protease inhibitors (PI) is a major obstacle to the full success of combined antiretroviral therapy. High-level resistance to these compounds is the consequence of stepwise accumulation of amino acid substitutions in the HIV-1 protease (PR), following pathways that usually differ from one inhibitor to another. The selective advantage conferred by resistance mutations may depend upon several parameters: the impact of the mutation on virus infectivity in the presence or absence of drug, the nature of the drug, and its local concentration. Because drug concentrations in vivo are subject to extensive variation over time and display a markedly uneven tissue distribution, the parameters of selection for HIV-1 resistance to PI in treated patients are complex and poorly understood. In this study, we have reconstructed a large series of HIV-1 mutants that carry single or combined mutations in the PR, retracing the accumulation pathways observed in ritonavir-, indinavir-, and saquinavir-treated patients. We have then measured the phenotypic resistance and the drug-free infectivity of these mutant viruses. A deeper insight into the evolutionary value of HIV-1 PR mutants came from a novel assay system designed to measure the replicative advantage of mutant viruses as a function of drug concentration. By tracing the resultant fitness profiles, we determined the range of drug concentrations for which mutant viruses displayed a replicative advantage over the wild type and the extent of this advantage. Fitness profiles were fully consistent with the order of accumulation of resistance mutations observed in treated patients and further emphasise the key importance of local drug concentration in the patterns of selection of drug-resistant HIV-1 mutants.
J Virol 2000 Sep
PMID:Retracing the evolutionary pathways of human immunodeficiency virus type 1 resistance to protease inhibitors: virus fitness in the absence and in the presence of drug. 1095 53

The recognition sequences for substrate cleavage by aspartic protease of HIV-1 are diverse and cleavage specificities are controlled by complex interactions between at least six amino acids around the cleavage site. We have identified 45 efficiently cleaved peptide substrates of HIV-1 protease (PR) using substrate phage display, an approach that can elucidate both context-dependent and context-independent preferences at individual subsites of a protease substrate. Many of the selected peptides were cleaved more efficiently and had lower K(m) values than physiologically relevant substrates of HIV-1 PR. Therefore, mutations occurring in the cleavage sites of the Gag and Gag-pol polyproteins of HIV-1 could significantly lower the K(m) values to better compete against drugs for protease binding while maintaining cleavage rates necessary for viral replication. The most efficiently cleaved peptide substrate derived from these phage, Ac-GSGIF*LETSL-NH(2), was cleaved 60 times more efficiently and had a K(m) approximately 260 times lower than a nine-amino-acid peptide based on the natural reverse transcriptase/integrase cleavage site when assayed at pH 5.6, 0.2 M NaCl. The peptide substrates selected served as frameworks for synthesis of tight binding reduced amide inhibitors of HIV-1 PR. The results show that the most efficiently cleaved substrates serve as the best templates for synthesis of the tightest binding inhibitors. Thus, defining changes in substrate preferences for drug-resistant proteases may aid in the development of more efficacious inhibitors.
Virology 2000 Sep 01
PMID:Identification of efficiently cleaved substrates for HIV-1 protease using a phage display library and use in inhibitor development. 1096 81

The crystal structure of an actual HIV-1 protease-substrate complex is presented at 2.0 A resolution (R-value of 19.7 % (R(free) 23.3 %)) between an inactive variant (D25N) of HIV-1 protease and a long substrate peptide, Lys-Ala-Arg-Val-Leu-Ala-Glu-Ala-Met-Ser, which covers a full binding epitope of capsid(CA)-p2, cleavage site. The substrate peptide is asymmetric in both size and charge distribution. To accommodate this asymmetry the two protease monomers adopt different conformations burying a total of 1038 A(2) of surface area at the protease-substrate interface. The specificity for the CA-p2 substrate peptide is mainly hydrophobic, as most of the hydrogen bonds are made with the backbone of the peptide substrate. Two water molecules bridge the two monomers through the loops Gly49-Gly52 (Gly49'-Gly52') and Pro79'-Val82' (Pro79-Val82). When other complexes are compared, the mobility of these loops is correlated with the content of the P1 and P1' sites. Interdependence of the conformational changes allows the protease to exhibit its wide range of substrate specificity.
J Mol Biol 2000 Sep 01
PMID:How does a symmetric dimer recognize an asymmetric substrate? A substrate complex of HIV-1 protease. 1096 16

Salvage therapy with ritonavir (RTV) and saquinavir (SQV) failed to achieve virological and immunological improvement in 24 HIV-infected patients who discontinued triple therapy with RTV or indinavir (IDV) because of failure or intolerance to treatment. Changes in the HIV-1 protease gene sequence were analyzed prospectively in 14 patients. No primary protease mutation was found prior to the use of protease inhibitors. After 7 months of treatment with IDV or RTV, primary resistance mutations at codons pol 46 and/or pol 82 were observed in 11 of 13 patients. After 16 weeks on RTV-SQV, novel primary mutations related to SQV emerged in 7 of 13 patients, together with an increase in the number of secondary resistance mutations. Our observations indicate that the cumulative occurrence of resistance mutations in the protease gene was associated with failure of antiretroviral therapy. The presence of mutations to a first protease inhibitor may represent a risk factor for the failure of a subsequent treatment with a second line protease inhibitor.
Antiviral Res 2000 Sep
PMID:The cumulative occurrence of resistance mutations in the HIV-1 protease gene is associated with failure of salvage therapy with ritonavir and saquinavir in protease inhibitor-experienced patients. 1097 70


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