Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

To investigate the biochemical properties of the protease encoded by the human endogenous retrovirus, K10 (HERV-K), 213 amino acids of the 3'-end of the HERV-K protease (PR) open reading frame were expressed in Escherichia coli. Autocatalytic cleavage of the expressed polypeptide resulted in an 18.2 kDa protein which was shown to be proteolytically active against a fluorogenic peptide used as a substrate for HIV-1 protease. On the basis of sequence homology and molecular modeling, the 106 N-terminal amino acids of HERV-K PR were predicted to comprise a retroviral protease core domain. An 11.6 kDa protein corresponding to this region was expressed and shown to be a fully functional enzyme. The 11.6 kDa domain of HERV-K PR is unusually stable over a wide pH range, exhibits optimal catalytic activity between pH 4.0 and 5.0, and exists as a dimer at pH 7.0 with a Kd of 50 microM. Like HIV-1 PR, the HERV-K PR core domain is activated by high salt concentrations and processes HIV-1 matrix-capsid polyprotein at the authentic HIV-1 PR recognition site. However, both the 18.2 and 11.6 kDa forms of HERV-K PR were highly resistant to a number of clinically useful HIV-1 PR inhibitors, including ritonavir, indinavir, and saquinavir. This raises the possibility that HERV-K PR may complement HIV-1 PR during infection, and could have implications for protease inhibitor therapy and drug resistance.
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PMID:Functional characterization of the protease of human endogenous retrovirus, K10: can it complement HIV-1 protease? 986 Aug 26

Resistance to the HIV-1 protease inhibitor indinavir involves the accumulation of multiple amino acid substitutions in the viral protease. A minimum of 11 amino acid positions have been identified as potential contributors to phenotypic resistance. Three or more amino acid substitutions in the protease are required before resistance becomes measurable (> or = four-fold). Further losses in susceptibility follow the stepwise accumulation of additional amino acid substitutions, indicating that antiviral activity (selective pressure) is maintained despite the appearance of multiple amino acid substitutions in the viral protease. Importantly, the sequential nature of these changes indicates that the effects of these substitutions are additive, and that the evolution of resistance is driven by viral replication. This result has significant implications for therapy. It predicts that viral variants resistant to indinavir are unlikely to pre-exist in protease inhibitor-naive patients, and further, that high-level resistance can only develop if the virus is allowed to replicate in the presence of the drug. The use of indinavir in combination with other antiretroviral agents has been demonstrated to dramatically reduce the incidence of resistance mutations, suggesting that with maximal suppression of viral replication, long-term control of HIV-1 infection may be achievable. Thus, the goal of therapy must be to never to allow the virus to replicate. This can be best accomplished by initiating therapy with a maximally suppressive regimen, to reduce viral replication as much as possible, and by imposing a high genetic barrier to resistance. Previous use of other protease inhibitors or inadequate adherence to therapy may compromise the long-term benefit of indinavir by allowing the virus to gain a foothold through the development of resistance. An understanding of these issues will be critical in realizing the full potential of this potent new drug for the control of HIV-1 infection.
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PMID:Resistance to HIV protease inhibitors. 987 2

Multidrug antiretroviral regimens that include human immunodeficiency virus-1 (HIV-1) protease inhibitors are associated with distinct lipodystrophy, hypertriglyceridemia, hyperinsulinemia, and deposition of visceral abdominal adipose tissue. To determine whether these findings are related to abnormalities of adrenal function, we compared the hypothalamic-pituitary-adrenal axes of HIV-positive patients who had evidence of protease inhibitor-associated lipodystrophy (PIAL), control volunteers (CON), and patients with Cushing's syndrome (CS). To elucidate the metabolic consequences of the observed lipodystrophy, we measured basal serum lipids and compared glucose and insulin concentrations during an oral glucose tolerance test. Spontaneous plasma cortisol showed normal diurnal variation in PIAL. Cortisol levels were similar in CON and PIAL, and levels in these groups were less than those in CS at all times of the night or day (P < 0.005). Ovine CRH-stimulated morning plasma cortisol levels were similar in PIAL and CON. ACTH was significantly greater in PIAL than CON (P < 0.05) at 0, 15, and 30 min after CRH stimulation. Urinary free cortisol in PIAL (mean +/- SD, 76 +/- 51 nmol/day) was significant lower than those in CON (165 +/- 64 nmol/day; P < 0.001) and CS (1715 +/- 1203 nmol/day; P < 0.001). However, 17-hydroxycorticosteroid excretion was significantly greater in PIAL (43 +/- 23 micromol/day) than in CON (17 +/- 8 micromol/day; P < 0.001), although lower than that in CS (74 +/- 47 micromol/day; P < 0.01). Scatchard analysis revealed normal glucocorticoid receptor number and affinity in PIAL. Serum triglycerides were significantly greater in PIAL (6.57 +/- 5.63 mmol/L) than in CS (1.78 +/- 0.83 mmol/L; P < 0.001) or CON (1.36 +/- 0.84 mmol/L; P < 0.001). Although triglyceride levels were significantly correlated with body mass index for CON and CS, these were not correlated for PIAL. During an oral glucose tolerance test, similar glucose and insulin values were found in PIAL and CS that were greater (P < 0.05) than CON values at 30, 60, 90, and 120 min. We conclude that the lipodystrophy associated with use of HIV-1 protease inhibitors is a syndrome of increased intraabdominal adiposity with concomitant dyslipidemia and insulin resistance, but without total body weight gain and is distinct from any known form of hypercortisolism. Although urinary cortisol disposition seems to be altered in HIV-infected patients who are being treated with multidrug regimens that include protease inhibitors, the decreased free cortisol and increased 17-hydroxycorticosteroid excretion appear to be unlikely explanations for the observed lipodystrophy. The cause remains to be elucidated.
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PMID:Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy. 1037 88

The human immunodeficiency virus (HIV) codes for an aspartic protease known to be essential for retroviral maturation and replication. HIV protease is formed from two identical 99 amino acid peptides. We synthesized [(NHCH2CH2-S-CH2CO)51-52, Ala67,95]HIV-1 protease using the thioether chemical ligation method, and then prepared the [(NHCH2CH2-S-CH2CO)51-52, Ala67,95, Cys98]HIV-1 protease dimer analogue covalently linked by a disulfide bridge. These HIV-1 protease analogues effectively cleaved the Tyr-Phe-type substrate, but had weak affinity to the Tyr-Pro-type substrate. Consequently, the molecular recognition of the protease analogues differs from that of the wild-type enzyme. Based on the substrate transition state, we designed and synthesized a novel class of HIV protease inhibitors containing an unnatural amino acid, (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid, named allophenylnorstatine, with a hydroxymethylcarbonyl (HMC) isostere. The stereochemistry of the hydroxyl group was significant for the enzyme inhibition and the HMC group interacted excellently with the aspartic acid carboxyl groups of HIV protease active site in the essentially same hydrogen-bonding mode as the transition state. Small dipeptide-based HIV protease inhibitors containing the HMC isostere were studied as advantageous compounds. Among them, a dipeptide-based HIV protease inhibitor, KNI-577, exhibited potent antiviral activities, low cytotoxicity, and good pharmacokinetic properties.
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PMID:Small dipeptide-based HIV protease inhibitors containing the hydroxymethylcarbonyl isostere as an ideal transition-state mimic. 1038 Mar 53

Various analogs of statine, a remarkable amino acid component of the protease inhibitor pepstatine, were synthesized and evaluated as tripeptide derivatives for their activity against cathepsin D and HIV-1 protease.
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PMID:Inhibition of cathepsin D by tripeptides containing statine analogs. 1042 75

Many patients infected with human immunodeficiency virus type 1 (HIV-1) have suboptimal responses to protease inhibitor-based therapy. We retrospectively evaluated a cohort of 104 HIV-positive adults, most of whom had previously received antiretrovirals, to identify the frequency and clinical predictors of incomplete response to potent HIV-1 protease inhibitors. Sixty-two (60%) of the patients had an incomplete response, defined as a plasma HIV-1 RNA level of >400 copies/mL after 20 weeks of therapy. Logistic regression analysis identified the following independent risk factors for incomplete response: elevated baseline plasma HIV-1 RNA level (P = .03), low baseline weight (P = .01), chemoprophylaxis for Pneumocystis carinii pneumonia (P = .04), and active illicit drug use (P = .04). Regular prescription of narcotics or benzodiazepine anxiolytics (P = .01) and use of any Internet site (P = .01) predicted a more favorable response. Identifying factors that predict suboptimal response to protease inhibitors improves our understanding of interpatient variability in response to therapy and should foster strategies that enhance the effectiveness of current and future regimens.
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PMID:Factors that predict incomplete virological response to protease inhibitor-based antiretroviral therapy. 1067 60

Three high level, cross-resistant variants of the HIV-1 protease have been analyzed for their ability to bind four protease inhibitors approved by the Food and Drug Administration (saquinavir, ritonavir, indinavir, and nelfinavir) as AIDS therapeutics. The loss in binding energy (DeltaDeltaG(b)) going from the wild-type enzyme to mutant enzymes ranges from 2.5 to 4.4 kcal/mol, 40-65% of which is attributed to amino acid substitutions away from the active site of the protease and not in direct contact with the inhibitor. The data suggest that non-active site changes are collectively a major contributor toward engendering resistance against the protease inhibitor and cannot be ignored when considering cross-resistance issues of drugs against the HIV-1 protease.
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PMID:Non-active site changes elicit broad-based cross-resistance of the HIV-1 protease to inhibitors. 1044 27

In order to analyze the impact of protease gene polymorphism on response to regimens containing a protease inhibitor, the entire protease coding domain from 58 human immunodeficiency virus type 1 (HIV-1)-infected patients who were protease inhibitor naive was sequenced before therapy was started. Plasma HIV-1 RNA levels were measured at baseline and at month 3 and month 6 after treatment. All patients were treated with a combination of two reverse transcriptase inhibitors and a protease inhibitor (saquinavir EOF [n = 28], ritonavir [n = 16], or indinavir [n = 14]). Before treatment, 30 different positions whose codons differed from the subtype B consensus sequence were observed. Major mutations associated with protease inhibitor resistance were not observed. No statistical correlation between the number of amino acid differences and the treatment efficacy at month 3 (-2.4 log) or month 6 (-2.7 log) was observed. At baseline, genotypic analysis of the HIV-1 protease gene of patients who have never received a protease inhibitor does not allow prediction of the efficacy of regimens containing a protease inhibitor.
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PMID:Polymorphism of the human immunodeficiency virus type 1 (HIV-1) protease gene and response of HIV-1-infected patients to a protease inhibitor. 1044 74

Changes in human immunodeficiency virus (HIV) type 1 concentration and protease genotype were evaluated in semen specimens from 22 HIV-positive men before and 6 months after the addition of indinavir to dual nucleoside therapy. Seminal HIV was detected by polymerase chain reaction analysis for DNA or RNA for 59% of men before combination treatment and persisted at 6 months for 31% of the men who initially had seminal HIV detected (P = .026). The maximum levels of cell-free RNA, cell-associated RNA, and proviral DNA in semen before treatment and at 6 months were 400,000 and 10,000 copies/mL, 70,000 and 27,000 copies/mL, and 80,000 and 3,000 copies/mL, respectively. Three of the four men with persistent seminal DNA had plasma viral loads of > 10,000 copies/mL before treatment. One patient who became intolerant to indinavir had seminal HIV RNA detected by PCR analysis after 6 months. Although none of the cultures of semen specimens from the four men with PCR analysis-detectable seminal DNA after 6 months yielded HIV, indinavir resistance mutations were identified in a seminal leukocyte DNA specimen from one patient, and a second patient whose therapy was switched to saquinavir had different protease inhibitor resistance mutations in seminal and blood leukocyte DNA specimens. HIV-1 protease inhibitor resistance mutants may emerge in the semen of patients receiving combination therapy.
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PMID:Persistence of human immunodeficiency virus in semen after adding indinavir to combination antiretroviral therapy. 1045 Nov 62

A significant number of adult male patients with acquired immunodeficiency syndrome develop cerebral atrophy and progressive brain disorders such as dementia complex and neuropsychiatric problems. Upon entering the brain via activated macrophages or microglias, the human immunodeficiency type 1 virus (HIV-1) may produce cytotoxic factors such as HIV-1 envelope protein (gp120) and protease. Owing to significant proteolysis of nonviral proteins, the protease derived from HIV-1 may be detrimental to brain cells and neurons. Our results revealed that HIV-1 protease, at nanomolar concentrations, was as potent as gp120 in causing neurotoxicity in human neuroblastoma neurotypic SH-SY5Y cells. As shown by the Oncor ApopTag staining procedure, HIV-1 protease significantly increased the number of apoptotic cells over the serum-free controls. Moreover, HIV-1 protease-induced neurotoxicity was blocked by a selective protease inhibitor, kynostatin (KNI-272). Antioxidants such as 17beta-estradiol, melatonin, and S-nitrosoglutathione also prevented protease-induced neurotoxicity. These findings indicate that oxidative proteolysis may mediate HIV-1 protease-induced apoptosis and the degeneration of neurons and other brain cells. Centrally active protease inhibitors and antioxidants may play an important role in preventing cerebral atrophy and associated dementia complex caused by HIV-1.
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PMID:Kynostatin and 17beta-estradiol prevent the apoptotic death of human neuroblastoma cells exposed to HIV-1 protease. 1054 79


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