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The New England Journal of Medicine Apr 2022Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M) inhibitor with potent pan-human-coronavirus activity in vitro. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M) inhibitor with potent pan-human-coronavirus activity in vitro.
METHODS
We conducted a phase 2-3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19-related hospitalization or death from any cause through day 28, viral load, and safety were evaluated.
RESULTS
A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], -9.04 to -3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of -5.81 percentage points (95% CI, -7.78 to -3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmatrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo.
CONCLUSIONS
Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.).
Topics: Adult; Humans; Administration, Oral; Antiviral Agents; COVID-19 Drug Treatment; Disease Progression; Double-Blind Method; Hospitalization; Lactams; Leucine; Nitriles; Proline; Ritonavir; SARS-CoV-2; Treatment Outcome; Vaccination; Viral Load; Viral Protease Inhibitors; COVID-19
PubMed: 35172054
DOI: 10.1056/NEJMoa2118542 -
Science (New York, N.Y.) Sep 2020The coronavirus disease 2019 (COVID-19) pandemic has led to accelerated efforts to develop therapeutics and vaccines. A key target of these efforts is the spike (S)...
The coronavirus disease 2019 (COVID-19) pandemic has led to accelerated efforts to develop therapeutics and vaccines. A key target of these efforts is the spike (S) protein, which is metastable and difficult to produce recombinantly. We characterized 100 structure-guided spike designs and identified 26 individual substitutions that increased protein yields and stability. Testing combinations of beneficial substitutions resulted in the identification of HexaPro, a variant with six beneficial proline substitutions exhibiting higher expression than its parental construct (by a factor of 10) as well as the ability to withstand heat stress, storage at room temperature, and three freeze-thaw cycles. A cryo-electron microscopy structure of HexaPro at a resolution of 3.2 angstroms confirmed that it retains the prefusion spike conformation. High-yield production of a stabilized prefusion spike protein will accelerate the development of vaccines and serological diagnostics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Topics: Amino Acid Substitution; Betacoronavirus; COVID-19 Vaccines; Coronavirus Infections; Cryoelectron Microscopy; Humans; Proline; Protein Domains; Protein Stability; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Viral Vaccines
PubMed: 32703906
DOI: 10.1126/science.abd0826 -
JCI Insight Aug 2023Proline and its synthesis enzyme pyrroline-5-carboxylate reductase 1 (PYCR1) are implicated in epithelial-mesenchymal transition (EMT), yet how proline and PYCR1...
Proline and its synthesis enzyme pyrroline-5-carboxylate reductase 1 (PYCR1) are implicated in epithelial-mesenchymal transition (EMT), yet how proline and PYCR1 function in allergic asthmatic airway remodeling via EMT has not yet been addressed to our knowledge. In the present study, increased levels of plasma proline and PYCR1 were observed in patients with asthma. Similarly, proline and PYCR1 in lung tissues were high in a murine allergic asthma model induced by house dust mites (HDMs). Pycr1 knockout decreased proline in lung tissues, with reduced airway remodeling and EMT. Mechanistically, loss of Pycr1 restrained HDM-induced EMT by modulating mitochondrial fission, metabolic reprogramming, and the AKT/mTORC1 and WNT3a/β-catenin signaling pathways in airway epithelial cells. Therapeutic inhibition of PYCR1 in wild-type mice disrupted HDM-induced airway inflammation and remodeling. Deprivation of exogenous proline relieved HDM-induced airway remodeling to some extent. Collectively, this study illuminates that proline and PYCR1 involved with airway remodeling in allergic asthma could be viable targets for asthma treatment.
Topics: Animals; Mice; Airway Remodeling; Proline; Asthma; Lung; Hypersensitivity
PubMed: 37432745
DOI: 10.1172/jci.insight.167395 -
Science (New York, N.Y.) Dec 2021The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral...
The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.
Topics: Administration, Oral; Animals; COVID-19; Clinical Trials, Phase I as Topic; Coronavirus; Disease Models, Animal; Drug Therapy, Combination; Humans; Lactams; Leucine; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Nitriles; Proline; Randomized Controlled Trials as Topic; Ritonavir; SARS-CoV-2; Viral Protease Inhibitors; Virus Replication; COVID-19 Drug Treatment
PubMed: 34726479
DOI: 10.1126/science.abl4784 -
Frontiers in Endocrinology 2021Increasing evidence indicates that physical activity and exercise training may delay or prevent the onset of Alzheimer's disease (AD). However, systemic biomarkers that... (Randomized Controlled Trial)
Randomized Controlled Trial
Increasing evidence indicates that physical activity and exercise training may delay or prevent the onset of Alzheimer's disease (AD). However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking. To begin to address this issue, we utilized blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50% female) who underwent 26 weeks of supervised treadmill training. Systemic biomarkers implicated in learning and memory, including the myokine Cathepsin B (CTSB), brain-derived neurotrophic factor (BDNF), and klotho, as well as metabolomics were evaluated. Here we show that aerobic exercise training increases plasma CTSB and that changes in CTSB, but not BDNF or klotho, correlate with cognitive performance. BDNF levels decreased with exercise training. Klotho levels were unchanged by training, but closely associated with change in VOpeak. Metabolomic analysis revealed increased levels of polyunsaturated free fatty acids (PUFAs), reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis, with exercise. Multiple metabolites (~30%) correlated with changes in BDNF, but not CSTB or klotho. The positive association between CTSB and cognition, and the modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function. Overall, our analyses indicate metabolic regulation of exercise-induced plasma BDNF changes and provide evidence that CTSB is a marker of cognitive changes in late middle-aged adults at risk for dementia.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Brain-Derived Neurotrophic Factor; Cathepsin B; Cognition; Exercise; Fatty Acids, Omega-3; Female; Gastrointestinal Microbiome; Humans; Hydroxyproline; Klotho Proteins; Lipid Metabolism; Male; Metabolomics; Middle Aged; Proline; Risk Factors
PubMed: 34093436
DOI: 10.3389/fendo.2021.660181 -
The New Phytologist Jan 2023Drought stress limits wheat production and threatens food security world-wide. While ethylene-responsive factors (ERFs) are known to regulate plant response to drought...
Drought stress limits wheat production and threatens food security world-wide. While ethylene-responsive factors (ERFs) are known to regulate plant response to drought stress, the regulatory mechanisms responsible for a tolerant phenotype remain unclear. Here, we describe the positive regulatory role of TaERF87 in mediating wheat tolerance to drought stress. TaERF87 overexpression (OE) enhances drought tolerance, while silencing leads to drought sensitivity in wheat. RNA sequencing with biochemical assays revealed that TaERF87 activates the expression of the proline biosynthesis genes TaP5CS1 and TaP5CR1 via direct binding to GCC-box elements. Furthermore, proline accumulates to higher levels in TaERF87- and TaP5CS1-OE lines than that in wild-type plants under well-watered and drought stress conditions concomitantly with enhanced drought tolerance in these transgenic lines. Moreover, the interaction between TaERF87 and the bHLH transcription factor TaAKS1 synergistically enhances TaP5CS1 and TaP5CR1 transcriptional activation. TaAKS1 OE also increases wheat drought tolerance by promoting proline accumulation. Additionally, our findings verified that TaERF87 and TaAKS1 are targets of abscisic acid-responsive element binding factor 2 (TaABF2). Together, our study elucidates the mechanisms underlying a positive response to drought stress mediated by the TaABF2-TaERF87/TaAKS1-TaP5CS1/TaP5CR1 module, and identifies candidate genes for the development of elite drought-tolerant wheat varieties.
Topics: Droughts; Gene Expression Regulation, Plant; Plant Proteins; Plants, Genetically Modified; Proline; Stress, Physiological; Triticum; Drought Resistance
PubMed: 36264565
DOI: 10.1111/nph.18549 -
The New England Journal of Medicine Sep 2021Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar to human GLP-1 have been shown to reduce the risk of adverse cardiovascular events... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar to human GLP-1 have been shown to reduce the risk of adverse cardiovascular events among persons with type 2 diabetes. The effect of an exendin-based GLP-1 receptor agonist, efpeglenatide, on cardiovascular and renal outcomes in patients with type 2 diabetes who are also at high risk for adverse cardiovascular events is uncertain.
METHODS
In this randomized, placebo-controlled trial conducted at 344 sites across 28 countries, we evaluated efpeglenatide in participants with type 2 diabetes and either a history of cardiovascular disease or current kidney disease (defined as an estimated glomerular filtration rate of 25.0 to 59.9 ml per minute per 1.73 m of body-surface area) plus at least one other cardiovascular risk factor. Participants were randomly assigned in a 1:1:1 ratio to receive weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg or placebo. Randomization was stratified according to use of sodium-glucose cotransporter 2 inhibitors. The primary outcome was the first major adverse cardiovascular event (MACE; a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes).
RESULTS
A total of 4076 participants were enrolled; 2717 were assigned to receive efpeglenatide and 1359 to receive placebo. During a median follow-up of 1.81 years, an incident MACE occurred in 189 participants (7.0%) assigned to receive efpeglenatide (3.9 events per 100 person-years) and 125 participants (9.2%) assigned to receive placebo (5.3 events per 100 person-years) (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P<0.001 for noninferiority; P = 0.007 for superiority). A composite renal outcome event (a decrease in kidney function or macroalbuminuria) occurred in 353 participants (13.0%) assigned to receive efpeglenatide and in 250 participants (18.4%) assigned to receive placebo (hazard ratio, 0.68; 95% CI, 0.57 to 0.79; P<0.001). Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than with placebo.
CONCLUSIONS
In this trial involving participants with type 2 diabetes who had either a history of cardiovascular disease or current kidney disease plus at least one other cardiovascular risk factor, the risk of cardiovascular events was lower among those who received weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg than among those who received placebo. (Funded by Sanofi; AMPLITUDE-O ClinicalTrials.gov number, NCT03496298.).
Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Proline
PubMed: 34215025
DOI: 10.1056/NEJMoa2108269 -
The New England Journal of Medicine Sep 2022
Topics: Antiviral Agents; Drug Combinations; Humans; Lactams; Leucine; Nitriles; Proline; Recurrence; Ritonavir; Viral Load; COVID-19 Drug Treatment
PubMed: 36069818
DOI: 10.1056/NEJMc2205944 -
Journal of Wound Care Jan 2021We evaluated the effects of a specialised oral nutritional supplement (ONS) containing arginine and proline, with high vitamin A, C and E, zinc and selenium content, on... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
We evaluated the effects of a specialised oral nutritional supplement (ONS) containing arginine and proline, with high vitamin A, C and E, zinc and selenium content, on the repair of hard-to-heal wounds.
METHOD
Patients with hard-to-heal wounds were evaluated at five timepoints (S0-S4) over four consecutive weeks. At S0 patients were randomised to the specialised ONS (n=15; 25 wounds) or control (n=15; 25 wounds) groups. Posology was 200ml twice daily over the research period. Wound surface area and perimeter were monitored. In addition to the metric data, it was also possible to calculate the rate of wound contraction and the linear growth of the wound edges, looking for wound-healing predictive factors.
RESULTS
A total of 30 patients took part in the study. Mean age was 65 years and 50% of patients had diabetes. Of the total evaluated wounds, 78% were <50cm, 14% were 50-150cm and 8% were >250cm. In 96% of cases, the wounds were in the lower limbs. A statistically significant reduction (p=0.004) in surface area of the wounds due to the specialised ONS, with a performance peak between S1 and S2, was observed. This specialised ONS did not induce changes in blood pressure, blood glucose level or renal function. A mean weekly wound edge growth of 1.85mm in patients with diabetes and 3.0mm in those without diabetes was observed. These results were 2.9 and 4.6 times, respectively, higher than expected, according to the literature.
CONCLUSION
Specialised ONS can be a therapeutic option for hard-to-heal wounds.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Dietary Supplements; Female; Humans; Male; Middle Aged; Pressure Ulcer; Proline; Treatment Outcome; Wound Healing; Zinc
PubMed: 33439085
DOI: 10.12968/jowc.2021.30.1.26 -
Blood Nov 2021Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors...
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors prevent membrane attack complex formation, but patients may experience extravascular hemolysis (EVH) and continue to require blood transfusions. Danicopan, an oral proximal complement inhibitor of alternative pathway factor D (FD), is designed to control IVH and EVH. In a phase 2 dose-finding trial, eculizumab-treated transfusion-dependent patients with PNH (n = 12) received danicopan, 100 to 200 mg thrice daily, in addition to their eculizumab regimen for 24 weeks. End points included hemoglobin (Hgb) change vs baseline at week 24 (primary), reduction in blood transfusions, and patient-reported outcomes. Safety, tolerability, and pharmacokinetics/pharmacodynamics were measured. Twelve patients received ≥1 danicopan dose; 1 patients discontinued from a serious adverse event deemed unlikely related to danicopan. Eleven patients completed the 24-week treatment period. Addition of danicopan resulted in a mean Hgb increase of 2.4 g/dL at week 24. In the 24 weeks prior to danicopan, 10 patients received 31 transfusions (50 units) compared with 1 transfusion (2 units) in 1 patient during the 24-week treatment period. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score increased by 11 points from baseline to week 24. The most common adverse events were headache, cough, and nasopharyngitis. Addition of danicopan, a first-in-class FD inhibitor, led to a meaningful improvement in Hgb and reduced transfusion requirements in patients with PNH who were transfusion-dependent on eculizumab. These benefits were associated with improvement of FACIT-Fatigue. This trial was registered at www.clinicaltrials.gov as #NCT03472885.
Topics: Adult; Aged; Aminopyridines; Antibodies, Monoclonal, Humanized; Complement Inactivating Agents; Female; Hemoglobinuria, Paroxysmal; Humans; Indazoles; Male; Middle Aged; Proline; Pyrimidines; Treatment Outcome; Young Adult
PubMed: 34314483
DOI: 10.1182/blood.2021011388