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AIDS Reviews 2009Lopinavir/ritonavir has been the recommended boosted protease inhibitor for treatment-naive individuals in all guidelines since its approval in the year 2000. More... (Review)
Review
Lopinavir/ritonavir has been the recommended boosted protease inhibitor for treatment-naive individuals in all guidelines since its approval in the year 2000. More recently, the rest of ritonavir-boosted protease inhibitors (namely lopinavir once-daily, fosamprenavir, saquinavir, atazanavir, and darunavir) have demonstrated non-inferior antiviral efficacy at 48 weeks than lopinavir twice-daily. Overall, all ritonavir-boosted protease inhibitors display a high genetic and pharmacological barrier to resistance development and protect the rest of the drugs on board in the regimen, achieving similar CD4 count gains among them. During the last year, studies conducted with atazanavir and darunavir have demonstrated superior virologic efficacy against lopinavir at 96 weeks in their pivotal trials. These two protease inhibitors provide significant improvements in triglycerides and gastrointestinal toxicity, together with simpler once-daily formulations, compared to lopinavir. In the case of atazanavir, this is mainly driven by a lower rate of discontinuations due to drug-related side effects, as pure antiviral efficacy is essentially similar to lopinavir. Furthermore, the gastrointestinal intolerance of lopinavir is actually compensated by an increased risk of hyperbilirubinemia and jaundice with atazanavir, but this is more a cosmetic problem and rarely a cause of drug withdrawal. Darunavir has been licensed to be taken once-daily in treatment-naive patients, and shows significantly better lipid and gastrointestinal tolerance than lopinavir. Robust sensitivity analysis with darunavir prove superior antiviral efficacy than lopinavir at 96 weeks also when non-virologic failures (toxicity and discontinuations) are censored, or when only patients receiving lopinavir twice-daily are included in the estimation. Moreover, darunavir has shown superior antiviral efficacy than lopinavir, particularly in three situations of particular clinical concern: high baseline viral load, low baseline CD4 counts, and suboptimal drug adherence. Over the last years, the treatment landscape with ritonavir-boosted protease inhibitors as initial HIV therapy has accomplished significant advances, with improved degrees of efficacy, tolerability, and convenience, that should be used to guide treatment choice in first-line antiretroviral therapy.
Topics: Anti-Retroviral Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; HIV-1; HTLV-I Infections; Humans; Protease Inhibitors; Treatment Outcome; Viremia
PubMed: 19940948
DOI: No ID Found -
Clinics in Liver Disease Aug 2009Hepatitis C virus (HCV) is a major cause of chronic liver disease leading to death from liver failure or hepatocellular carcinoma. Hepatitis C is the most common... (Review)
Review
Hepatitis C virus (HCV) is a major cause of chronic liver disease leading to death from liver failure or hepatocellular carcinoma. Hepatitis C is the most common indication for liver transplantation worldwide and is a major cause of the increased incidence of hepatocellular cancer in the United States. The current paradigm for HCV treatment relies on pegylated interferon and ribavirin as agents that enhance endogenous mechanisms for viral clearance and are dependent on host factors. In patients with genotype 1 HCV infection, sustained viral response (SVR) rates remain suboptimal, with less than half of genotype 1-infected individuals going on to achieve SVR. This has led to a shift in the investigational focus for treatment of HCV toward specifically targeted antiviral therapy for HCV agents. This review focuses on boceprevir, a protease inhibitor, and discusses its mechanism of action, effects on HCV, and viral resistance.
Topics: Antiviral Agents; Drug Resistance, Viral; Female; Hepacivirus; Hepatitis C; Humans; Male; Middle Aged; Proline; Protease Inhibitors; Viral Nonstructural Proteins
PubMed: 19628159
DOI: 10.1016/j.cld.2009.05.008 -
The Journal of Antibiotics Aug 2016Photorhabdus luminescens is a bioluminescent entomopathogenic bacterium that undergoes phenotypic variation and lives in mutualistic association with nematodes of the...
Photorhabdus luminescens is a bioluminescent entomopathogenic bacterium that undergoes phenotypic variation and lives in mutualistic association with nematodes of the family Heterorhabditidae. The pair infects and kills insects, and during their coordinated lifecycle, the bacteria produce an assortment of specialized metabolites to regulate its mutualistic and pathogenic roles. As part of our search for new specialized metabolites from the Photorhabdus genus, we examined organic extracts from P. luminescens grown in an amino-acid-rich medium based on the free amino-acid levels found in the circulatory fluid of its common insect prey, the Galleria mellonella larva. Reversed-phase HPLC/UV/MS-guided fractionation of the culture extracts led to the identification of two new pyrazinone metabolites, lumizinones A (1) and B (2), together with two N-acetyl dipeptides (3 and 4). The lumizinones were produced only in the phenotypic variant associated with nematode development and insect pathogenesis. Their chemical structures were elucidated by analysis of 1D and 2D NMR and high-resolution ESI-QTOF-MS spectral data. The absolute configurations of the amino acids in 3 and 4 were determined by Marfey's analysis. Compounds 1-4 were evaluated for their calpain protease inhibitory activity, and lumizinone A (1) showed inhibition with an IC50 (half-maximal inhibitory concentration) value of 3.9 μm.
Topics: Amino Acids; Animals; Chromatography, High Pressure Liquid; Inhibitory Concentration 50; Lepidoptera; Magnetic Resonance Spectroscopy; Mass Spectrometry; Photorhabdus; Protease Inhibitors; Pyrazines; Spectrometry, Mass, Electrospray Ionization
PubMed: 27353165
DOI: 10.1038/ja.2016.79 -
Scientific Reports Nov 2019Modulating the tumor microenvironment to promote an effective immune response is critical in managing any type of tumor. Melanoma is an aggressive skin cancer and the...
Modulating the tumor microenvironment to promote an effective immune response is critical in managing any type of tumor. Melanoma is an aggressive skin cancer and the incidence rate is increasing worldwide. Potent protease inhibitors have recently been extensively researched as potential therapeutic agents against various cancers. EgKI-1 is a potent Kunitz type protease inhibitor identified from the canine tapeworm Echinococcus granulosus that has shown anti-cancer activities in vivo. In this study we show that EgKI-1 significantly reduced the growth of melanoma in the B16-F0 mouse model and was not toxic to normal surrounding tissue. Moreover, EgKI-1 treatment significantly reduced survivin expression levels and increased the CD8+ T cell population in draining axillary lymph nodes. Therefore, EgKI-1 potentially reduces tumor growth by inducing apoptosis and modulating the tumor microenvironment, and has potential for development as an intra-lesional treatment for melanoma.
Topics: Animals; Dogs; Echinococcus granulosus; Female; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Protease Inhibitors; Xenograft Model Antitumor Assays
PubMed: 31700040
DOI: 10.1038/s41598-019-52609-4 -
Journal of Molecular Graphics &... Jan 2023Human norovirus (HuNoV) causes acute viral gastroenteritis in all age groups, and dehydration and severe diarrhea in the elderly. The World Health Organization reports...
Human norovirus (HuNoV) causes acute viral gastroenteritis in all age groups, and dehydration and severe diarrhea in the elderly. The World Health Organization reports ∼1.45 million deaths from acute gastroenteritis annually in the world. Rupintrivir, an inhibitory medicine against the human rhinovirus C3 protease, has been reported to inhibit HuNoV 3C protease. However, several HuNoV 3C protease mutations have been revealed to reduce the susceptibility of HuNoV to rupintrivir. The structural details behind rupintrivir-resistance of these single-point mutations (A105V and I109V) are not still clear. Hence, in this study, a combination of computational techniques were used to determine the rupintrivir-resistance mechanism and to propose an inhibitor against wild-type and mutant HuNoV 3C protease through structure-based virtual screening. Dynamic structural results indicated the unstable binding of rupintrivir at the cleft binding site of the wild-type and mutant 3C proteases, leading to its detachment. Our findings presented that the domain II of the HuNoV 3C protease had a critical role in binding of inhibitory molecules. Binding energy computations, steered molecular dynamics and umbrella sampling simulations confirmed that amentoflavone, the novel suggested inhibitor, strongly binds to the cleft site of all protease models and has a good structural stability in the complex system along the molecular dynamic simulations. Our in silico study proposed the selected compound as a potential inhibitor against the HuNoV 3C protease. However, additional experimental and clinical studies are required to corroborate the therapeutic efficacy of the compound.
Topics: Humans; Antiviral Agents; Gastroenteritis; Norovirus; Peptide Hydrolases; Protease Inhibitors; Viral Proteins
PubMed: 36308946
DOI: 10.1016/j.jmgm.2022.108345 -
Drugs of Today (Barcelona, Spain : 1998) Nov 2005Tipranavir is a newly approved protease inhibitor that belongs to the class of 4-hydroxy-5,6-dyhydro-2-pyrones. It exhibits potent in vitro activity against both human... (Review)
Review
Tipranavir is a newly approved protease inhibitor that belongs to the class of 4-hydroxy-5,6-dyhydro-2-pyrones. It exhibits potent in vitro activity against both human immunodeficiency virus (HIV)-1 and HIV-2, including clinical isolates with multiple protease inhibitor-resistant mutations. Tipranavir requires coadministration with ritonavir to achieve clinically meaningful serum concentration. In randomized, phase III, open-label trials, it was found to be superior to the currently available boosted protease inhibitors in highly treatment-experienced patients with multiple protease inhibitor mutations. Thus, it provides a welcome new option for salvage antiretroviral therapy. The most common adverse effects associated with tipranavir are diarrhea, nausea and vomiting. Common laboratory abnormalities include elevations of total cholesterol, triglycerides and liver enzymes.
Topics: Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; HIV-1; HIV-2; Humans; Molecular Structure; Protease Inhibitors; Pyridines; Pyrones; Ritonavir; Sulfonamides; Treatment Outcome
PubMed: 16395412
DOI: 10.1358/dot.2005.41.11.937960 -
The Annals of Pharmacotherapy May 2011To review the use of telaprevir for the treatment of chronic hepatitis C. (Review)
Review
OBJECTIVE
To review the use of telaprevir for the treatment of chronic hepatitis C.
DATA SOURCES
Clinical studies were identified through MEDLINE (1966-January 2011), bibliographies of articles, clinicaltrials.gov, and fda.gov, using key words VX-950, telaprevir, and chronic hepatitis C.
STUDY SELECTION AND DATA EXTRACTION
Phase 1, 2, and 3 human and animal studies describing the pharmacology, pharmacokinetics, efficacy, and safety of telaprevir were identified. Additional articles were identified from the bibliographies of articles retrieved through MEDLINE.
DATA SYNTHESIS
Telaprevir is an NS3/4A protease inhibitor under investigation for the treatment of chronic hepatitis C virus (HCV) with pegylated interferon and ribavirin. Telaprevir competes with viral peptide substrates for the active site of NS3 and inhibits NS3-NS4A protease activity. Telaprevir has activity against HCV genotype 1 infection in vitro and in vivo, but monotherapy results in rapid viral resistance. In 3 Phase 2 and 3 Phase 3 randomized placebo-controlled trials, 12 weeks of telaprevir, along with varying durations of ribavirin treatment, induced higher sustained virologic response (SVR) compared with ribavirin alone. SVR was approximately 70% in treatment-naïve patients, 50-60% for patients in whom SVR had not occurred with prior ribavirin treatment, and 40-45% of those who received ribavirin alone. There was a high incidence of maculopapular rash (52% in 1 trial) and anemia (27% in 1 trial) in telaprevir-treated patients. The average dropout rate in Phase 3 trials as a result of adverse effects was 13%.
CONCLUSIONS
Twelve weeks of telaprevir with concomitant ribavirin treatment increases SVR for treatment-naïve and non-naïve patients with genotype 1 chronic HCV compared to 48 weeks of ribavirin treatment. Telaprevir may shorten the length of ribavirin therapy for some patients with extended rapid viral response, but viral mutations, adverse effects, and a high dropout rate may reduce the SVR seen in clinical practice.
Topics: Animals; Hepatitis C, Chronic; Humans; Oligopeptides; Protease Inhibitors; Randomized Controlled Trials as Topic; Viral Nonstructural Proteins
PubMed: 21558488
DOI: 10.1345/aph.1P430 -
International Journal of STD & AIDS Dec 2023Protease inhibitors (PIs) have contributed to the long-term survival of persons with human immunodeficiency virus (PHIV). While there is a concern linking protease...
BACKGROUND
Protease inhibitors (PIs) have contributed to the long-term survival of persons with human immunodeficiency virus (PHIV). While there is a concern linking protease inhibitors to an increased risk of heart failure (HF), the evidence linking protease inhibitors and heart failure has been uncertain.
METHODS
Following the PRISMA Extension for Scoping Reviews, we searched MEDLINE and EMBASE for peer-reviewed articles using keywords including "protease inhibitor," "heart failure," and "human immunodeficiency virus" from their inception to December 21, 2022.
RESULTS
Five articles, including three observational studies and two randomized controlled trials, were included in the review. While protease inhibitors seem to be associated with atherosclerotic cardiovascular disease through their effects on metabolic markers, there is scarce evidence suggesting a direct association between protease inhibitors and heart failure. Although one study showed a possible correlation between protease inhibitor use and lower left ventricular ejection fraction and increased heart failure admission, the results were subject to confounders, and participants had poor medication adherence.
CONCLUSION
Although current data are conflicting, there could be an association between PIs and HF in PHIV. Future prospective studies are warranted to evaluate the incidence of heart failure stratified on the generation of PIs and with adjustment for other metabolic risk factors.
Topics: Humans; Protease Inhibitors; Stroke Volume; Ventricular Function, Left; Heart Failure; Risk Factors; Antiviral Agents; HIV; Anti-Infective Agents
PubMed: 37608625
DOI: 10.1177/09564624231196599 -
Inflammation Apr 2015Protease(s) enhances airway inflammation and allergic cascade. In the present study, effect of a serine protease inhibitor was evaluated in mouse model of airway...
Protease(s) enhances airway inflammation and allergic cascade. In the present study, effect of a serine protease inhibitor was evaluated in mouse model of airway disease. Mice were sensitized with cockroach extract (CE) or Per a 10 and treated with 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) 1 h before or after challenge to measure airway response. Mice were euthanized to collect bronchoalveolar lavage fluid (BALF), blood, and lung to evaluate inflammation. AEBSF treatment significantly reduced the AHR in allergen-challenged mice in dose-dependent manner (p≤ 0.01). IgE (p≤0.05) and Th2 cytokines (p≤0.05) were significantly reduced in treated mice. AEBSF treatment lowered total cell (p≤0.05), eosinophil (p≤0.05), and neutrophil (p≤0.05) in BALF and lung tissue. Oxidative stress parameters were impaired on treatment in allergen-challenged mice (p≤0.05). AEBSF had therapeutic effect in allergen-induced airway resistance and underling inflammation and had potential for combination or as add-on therapy for respiratory diseases.
Topics: Allergens; Animals; Bronchoalveolar Lavage Fluid; Cockroaches; Disease Models, Animal; Female; Mice; Mice, Inbred BALB C; Oxidative Stress; Protease Inhibitors; Respiratory Hypersensitivity
PubMed: 25052477
DOI: 10.1007/s10753-014-9976-0 -
International Journal of Molecular... Mar 2022Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has been one of the most devastating pandemics of recent times. The... (Review)
Review
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has been one of the most devastating pandemics of recent times. The lack of potent novel antivirals had led to global health crises; however, emergence and approval of potent inhibitors of the viral main protease (Mpro), such as Pfizer's newly approved nirmatrelvir, offers hope not only in the therapeutic front but also in the context of prophylaxis against the infection. By their nature, RNA viruses including human immunodeficiency virus (HIV) have inherently high mutation rates, and lessons learnt from previous and currently ongoing pandemics have taught us that these viruses can easily escape selection pressure through mutation of vital target amino acid residues in monotherapeutic settings. In this paper, we review nirmatrelvir and its binding to SARS-CoV-2 Mpro and draw a comparison to inhibitors of HIV protease that were rendered obsolete by emergence of resistance mutations, emphasizing potential pitfalls in the design of inhibitors that may be of important relevance to the long-term use of novel inhibitors against SARS-CoV-2.
Topics: Antiviral Agents; Coronavirus 3C Proteases; HIV Protease; Humans; Molecular Docking Simulation; Peptide Hydrolases; Protease Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35408866
DOI: 10.3390/ijms23073507