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

It has been known that, in some cases, accumulation of specific mutations in HIV-1 protease leads to multi-protease inhibitor (PI) resistance. We examined the persistence of mutations detected in HIV-1 clinical isolates cross-resistant to the current PIs using an HIV-1 protease restricted library (HXB2 protease in an HIV-1(NL4-3) background) in the absence of protease inhibitors. The virus library contained combinations of 0-11 amino acid substitutions (4,096 possible combinations) in the protease-encoding region. We examined the frequency of each amino acid substitution in the library using a T cell line, MT-2. The frequency of the amino acid substitutions V82T/I and L90M decreased rapidly with a short half life (t(1/2) < 10 days). However, the mutations M36I, M46I and I84V were relatively persistent: t(1/2) = 34.2, 28.1 and 30.6 days, respectively. Other amino acid substitutions, i.e., L10I, I54V, L63P, A71V and V82A, were well retained (t(1/2) > 36 days). By contrast, the half lives (t(1/2)) of the D30N and N88D mutations associated with nelfinavir (NFV) resistance were only 7.2 and 1.8 days, respectively. These results indicate that this type of the HIV-1 protease restricted library is useful to evaluate the persistence of PI resistance-associated mutations in the absence of drug selective pressure.
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PMID:Persistence of mutations during replication of an HIV library containing combinations of selected protease mutations. 1516 98

This study aimed at identifying HIV-1 protease amino acid changes associated with protease inhibitor (PI) exposure and susceptibility. New amino acid substitutions were correlated with the number of experienced PIs, reaching statistical significance only for those at positions 3, 44, and 74. The correspondence multivariate model demonstrated that > or =3 experienced PIs and substitutions or mutations at positions 3, 46, 54, 73, 74, and 84 were correlated with PI cross-resistance, including resistance for lopinavir and amprenavir in this cohort of patients who were naive for these drugs.
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PMID:Drug resistance mutations and newly recognized treatment-related substitutions in the HIV-1 protease gene: prevalence and associations with drug exposure and real or virtual phenotypic resistance to protease inhibitors in two clinical cohorts of antiretroviral experienced patients. 1525 65

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

The mechanism by which chronic treatment with HIV (human immunodeficiency virus)-1 protease inhibitors leads to a deterioration of glucose metabolism appears to involve insulin resistance, and may also involve impaired insulin secretion. Here we investigated the long-term effects of HIV-1 protease inhibitors on glucose-stimulated insulin secretion from beta cells and explored whether altered insulin secretion might be related to altered insulin signaling. INS-1 cells were incubated for 48 h with different concentrations of amprenavir, indinavir, nelfinavir, ritonavir or saquinavir, stimulated with 20 mM d-glucose, and insulin determined in the supernatant. To evaluate insulin signaling, cells were stimulated with 100 nM insulin for 2 min, and insulin-receptor substrate (IRS)-1, -2 and Akt phosphorylation determined. Incubation for 48 h with ritonavir, nelfinavir and saquinavir resulted in impaired glucose-induced insulin secretion at 2.5, 5 and 5 microM respectively, whereas amprenavir or indinavir had no effects even at 20 and 100 microM respectively. The impaired insulin secretion by ritonavir, nelfinavir and saquinavir was associated with decreased insulin-stimulated IRS-2 phosphorylation, and, for nelfinavir and saquinavir, with decreased insulin-stimulated IRS-1 and Thr308-Akt phosphorylation. No such effects on signaling were observed with amprenavir or indinavir. In conclusion, certain HIV-1 protease inhibitors, such as ritonavir, nelfinavir and saquinavir, not only induce peripheral insulin resistance, but also impair glucose-stimulated insulin secretion from beta cells. With respect to the long-term effect on beta-cell function there appear to be differences between the protease inhibitors that may be clinically relevant. Finally, these effects on insulin secretion after a 48 h incubation with protease inhibitor were associated with a reduction of the insulin-stimulated phosphorylation of insulin signaling parameters, particularly IRS-2, suggesting that protease inhibitor-induced alterations in the insulin signaling pathway may contribute to the impaired beta-cell function.
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PMID:Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells. 1559 Sep 71

We have identified a rare HIV-1 protease (PR) mutation, I47A, associated with a high level of resistance to the protease inhibitor lopinavir (LPV) and with hypersusceptibility to the protease inhibitor saquinavir (SQV). The I47A mutation was found in 99 of 112,198 clinical specimens genotyped after LPV became available in late 2000, but in none of 24,426 clinical samples genotyped from 1998 to October 2000. Phenotypic data obtained for five I47A mutants showed unexpected resistance to LPV (86- to >110-fold) and hypersusceptibility to SQV (0.1- to 0.7-fold). Molecular modeling and energy calculations for these mutants using our structural phenotyping methodology showed an increase in the binding energy of LPV by 1.9-3.1 kcal/mol with respect to the wild type complex, corresponding to a 20- to >100-fold decrease in binding affinity, consistent with the observed high levels of LPV resistance. In the WT PR-LPV complex, the Ile 47 side chain is positioned close to the phenoxyacetyl moiety of LPV and its van der Waals interactions contribute significantly to the ligand binding. These interactions are lost for the smaller Ala 47 residue. Calculated binding energy changes for SQV ranged from -0.4 to -1.2 kcal/mol. In the mutant I47A PR-SQV complexes, the PR flaps are packed more tightly around SQV than in the WT complex, resulting in the formation of additional hydrogen bonds that increase binding affinity of SQV consistent with phenotypic hypersusceptibility. The emergence of mutations at PR residue 47 strongly correlates with increasing prescriptions of LPV (Spearman correlation r(s) = 0.96, P < .0001).
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PMID:Structural analysis of an HIV-1 protease I47A mutant resistant to the protease inhibitor lopinavir. 1593 77

A two-amino acid insertion near codon 70 of the HIV-1 protease gene was found in an individual failing protease inhibitor therapy. Susceptibility of this strain to protease inhibitors was similar to that of non-insert-containing strains with comparable resistance mutations and one or more other major PI mutations.
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PMID:New two-amino acid insertion near codon 70 of the HIV type 1 protease gene. 1594 74

Tipranavir is a non-peptidic HIV-1 protease inhibitor. It binds strongly and selectively, has a favourable resistance profile, and is administered orally twice daily with a subtherapeutic dosage of ritonavir in a 'boosted' regimen (TPV/r) in order to increase its bioavailability. Analysis of clinical isolates from treatment-experienced patients identified the following tipranavir resistance-associated HIV protease mutations: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, I84V. In two large, well designed phase III trials in protease inhibitor-experienced, HIV-infected patients, the RESIST (Randomised Evaluation of Strategic Intervention in multidrug reSistant patients with Tipranavir)-1 and -2 studies, oral TPV/r 500mg/200mg twice daily achieved a significantly better virological response after 24 weeks than standard ritonavir-boosted protease inhibitors. This held true for the proportion of patients achieving a >or=1 log(10) decrease in plasma HIV-RNA levels (viral load) [42% and 41% vs 22% and 15%; both p < 0.0001; primary endpoint] and other virological parameters (the proportion of patients with undetectable viral load and total viral load reduction). In addition, a significantly larger increase in CD4+ cell count was achieved with TPV/r than comparator regimens in these trials. The most common adverse events in clinical trials of tipranavir were gastrointestinal. The incidence of treatment discontinuation because of adverse events in the RESIST trials was 8% (pooled data).
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PMID:Tipranavir: a ritonavir-boosted protease inhibitor. 1606 Jul

Amprenavir is an oral, non-peptidic HIV-protease inhibitor undergoing phase III trials for the treatment of HIV and AIDS. In October 1998, Glaxo Wellcome submitted a new drug application (NDA) for amprenavir (Agenerase) in the US and Canada for which there is an April 1999 review deadline and in November 1998, filed an application for market approval in Europe. This product has been designated for fast-track approval. Merrill Lynch anticipates product launch in mid-1999 and estimates that Agenerase will reach peak sales of $500M after its launch. Amprenavir is a small molecule with significant aqueous solubility designed to combine antiviral potency with good oral bioavailability. The compound is a potent and specific inhibitor of isolated HIV-1 protease and of HIV-1 replication in T-cells and shows good absorption after oral dosage in man. The plasma half-life of amprenavir is approximately 10 h, allowing for twice daily dosing. The drug appears to cross the blood-brain barrier which may be an important feature in long-term treatment. Amprenavir selects for a unique mutation in the HIV-1 protease gene in vitro, and shows no or limited cross-resistance to other protease inhibitors. In January 1999 Paribas predicted Glaxo sales of pound sterling 75 million in 1999 rising to pound sterling 400 million in 2003.
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PMID:Amprenavir (Vertex Pharmaceuticals Inc). 1615 50

Due to factors such as resistance and long-term side effects as well as dosing regimen-related adherence issues, HIV therapy is a constantly moving target. HIV-1 protease inhibitors had an immediate and dramatic impact on the outcome of HIV/AIDS when launched in late 1995, and the search for new and improved next generation molecules has been under way in many laboratories. At GlaxoSmithKline (GSK) and Vertex Pharmaceuticals, this effort focused on two key issues, patient compliance and viral resistance. Using a water-solubilizing prodrug approach, the pill-burden in delivering our protease inhibitor, amprenavir, was dramatically decreased. By eliminating the large amounts of excipients necessary for the original soft-gel formulation, fosamprenavir (Lexiva/Telzir) delivers the clinically efficacious dose of amprenavir with two compact tablets per dose, compared to eight gel capsules. Our efforts to overcome viral resistance to 1(st) generation protease inhibitors by further elaborating the SAR of the amprenavir and related scaffolds, led to successive and dramatic improvements in wild-type antiviral potencies, and ultimately to the discovery of "ultra-potent" molecules with very favorable overall resistance profiles. The selection of GW640385 (brecanvir--USAN approved only) as a clinical candidate and its progression into current phase 2 dose ranging studies represents the culmination of our effort toward next generation protease inhibitors.
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PMID:Discovery of next generation inhibitors of HIV protease. 1637 44

The development of resistance to anti-retroviral drugs targeted against HIV is an increasing clinical problem in the treatment of HIV-1-infected individuals. Many patients develop drug-resistant strains of the virus after treatment with inhibitor cocktails (HAART therapy), which include multiple protease inhibitors. Therefore, it is imperative that we understand the mechanisms by which the viral proteins, in particular HIV-1 protease, develop resistance. We have determined the three-dimensional structure of HIV-1 protease NL4-3 in complex with the potent protease inhibitor TL-3 at 2.0 A resolution. We have also obtained the crystal structures of three mutant forms of NL4-3 protease containing one (V82A), three (V82A, M46I, F53L) and six (V82A, M46I, F53L, V77I, L24I, L63P) point mutations in complex with TL-3. The three protease mutants arose sequentially under ex vivo selective pressure in the presence of TL-3, and exhibit fourfold, 11-fold, and 30-fold resistance to TL-3, respectively. This series of protease crystal structures offers insights into the biochemical and structural mechanisms by which the enzyme can overcome inhibition by TL-3 while recovering some of its native catalytic activity.
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PMID:Structural insights into the mechanisms of drug resistance in HIV-1 protease NL4-3. 1640 21


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