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P2X3-selective mechanism of Gefapixant, a drug candidate for the treatment of refractory chronic cough.

ABSTRACT: Gefapixant/AF-219, a selective inhibitor of the P2X3 receptor, is the first new drug other than dextromethorphan to be approved for the treatment of refractory chronic cough (RCC) in nearly 60 years. To date, seven P2X subtypes (P2X1-7) activated by extracellular ATP have been cloned, and subtype selectivity of P2X inhibitors is a prerequisite for reducing side effects. We previously identified the site and mechanism of action of Gefapixant/AF-219 on the P2X3 receptor, which occupies a pocket consisting of the left flipper (LF) and lower body (LB) domains. However, the mechanism by which AF-219 selectively acts on the P2X3 receptor is unknown. Here, we combined mutagenesis, chimera construction, molecular simulations, covalent occupation and chemical synthesis, and find that the negative allosteric site of AF-219 at P2X3 is also present in other P2X subtypes, at least for P2X1, P2X2 and P2X4. By constructing each chimera of AF-219 sensitive P2X3 and insensitive P2X2 subtypes, the insensitive P2X2 subtype was made to acquire the inhibitory properties of AF-219 and AF-353, an analog of AF-219 with higher affinity. Our results suggest that the selectivity of AF-219/AF-353 for P2X3 over the other P2X subtypes is determined by a combination of the accessibility of P2X3 binding site and the internal shape of this pocket, a finding that could provide new perspectives for drug design against P2X3-mediated diseases such as RCC, idiopathic pulmonary fibrosis, hypertension and overactive bladder disorder.

SUBMITTER: Cui WW

PROVIDER: S-EPMC9014320 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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P2X3-selective mechanism of Gefapixant, a drug candidate for the treatment of refractory chronic cough.

Cui Wen-Wen WW Wang Si-Yu SY Zhang Yu-Qing YQ Wang Yao Y Fan Ying-Zhe YZ Guo Chang-Run CR Li Xing-Hua XH Lei Yun-Tao YT Wang Wen-Hui WH Yang Xiao-Na XN Hattori Motoyuki M Li Chang-Zhu CZ Wang Jin J Yu Ye Y

Computational and structural biotechnology journal 20220331

Gefapixant/AF-219, a selective inhibitor of the P2X3 receptor, is the first new drug other than dextromethorphan to be approved for the treatment of refractory chronic cough (RCC) in nearly 60 years. To date, seven P2X subtypes (P2X1-7) activated by extracellular ATP have been cloned, and subtype selectivity of P2X inhibitors is a prerequisite for reducing side effects. We previously identified the site and mechanism of action of Gefapixant/AF-219 on the P2X3 receptor, which occupies a pocket co ...[more]

PMID: 35465163

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Project description:ImportanceGefapixant represents an emerging therapy for patients with refractory or unexplained chronic cough.ObjectiveTo evaluate the efficacy and tolerability of gefapixant for the treatment of adults with refractory or unexplained chronic cough.Data sourcesMEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science from November 2014 to July 2023.Study selectionTwo reviewers independently screened for parallel and crossover randomized clinical trials (RCTs) that compared, in patients with refractory or unexplained chronic cough, either gefapixant with placebo, or 2 or more doses of gefapixant with or without placebo.Data extraction and synthesisTwo reviewers independently extracted data. A frequentist random-effects dose-response meta-analysis or pairwise meta-analysis was used for each outcome. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in whether patients would perceive the effects as important (greater than the minimal important difference [MID]) or small (less than the MID).Main outcomes and measuresCough frequency (measured using the VitaloJAK cough monitor; MID, 20%), cough severity (measured using the 100-mm visual analog scale [VAS]; higher score is worse; MID, 30 mm), cough-specific quality of life (measured using the Leicester Cough Questionnaire [LCQ]; score range, 3 [maximal impairment] to 21 [no impairment]; MID, 1.3 points), treatment-related adverse events, adverse events leading to discontinuation, and taste-related adverse events.ResultsNine RCTs including 2980 patients were included in the primary analysis. Compared with placebo, gefapixant (45 mg twice daily) had small effects on awake cough frequency (17.6% reduction [95% CI, 10.6%-24.0%], moderate certainty), cough severity on the 100-mm VAS (mean difference, -6.2 mm [95% CI, -4.1 to -8.4]; high certainty), and cough-specific quality of life on the LCQ (mean difference, 1.0 points [95% CI, 0.7-1.4]; moderate certainty). Compared with placebo, gefapixant (45 mg twice daily) probably caused an important increase in treatment-related adverse events (32 more per 100 patients [95% CI, 13-64 more], moderate certainty) and taste-related adverse events (32 more per 100 patients [95% CI, 22-46 more], high certainty). High-certainty evidence suggests that gefapixant (15 mg twice daily) had small effects on taste-related adverse events (6 more per 100 patients [95% CI, 5-8 more]).Conclusions and relevanceCompared with placebo, gefapixant (45 mg orally twice daily) led to modest improvements in cough frequency, cough severity, and cough-specific quality of life but increased taste-related adverse events.

Project description:IntroductionAvailable therapies for acute cough, a condition frequently caused by a viral upper respiratory tract infection (URTI), have shown limited evidence of efficacy. Gefapixant, a P2X3-receptor antagonist, has demonstrated efficacy and safety in studies of the treatment of refractory or unexplained chronic cough, but its efficacy for treating acute cough has not been previously studied.MethodsThis was a phase 2a, randomized, double-blind, placebo-controlled, parallel-group, pilot study. Healthy volunteers were randomized 1:1 to receive twice-daily gefapixant 45 mg or placebo and inoculated with human rhinovirus 16 to induce URTI and cough. Participants were observed while quarantined for 7 days after the start of treatment. The primary endpoint was awake cough frequency on day 3, which was objectively measured with a cough-recording device. Secondary endpoints included change from baseline to day 3 in subjective cough severity measures (cough severity visual analog scale, Cough Severity Diary) and cough-specific quality of life (Leicester Cough Questionnaire-acute).ResultsOf the 46 participants who met inclusion criteria [mean (standard deviation, SD) age, 24.6 (6.5) years; females, n = 8], 40 completed the study (gefapixant, n = 21; placebo, n = 19). There was no significant difference in awake cough frequency on day 3 between the gefapixant and placebo groups [least squares means, 2.4 versus 2.7 coughs per hour, respectively; mean difference (95% confidence interval, CI), -0.3 (-2.3, 1.7); P = 0.75]. There were no significant between-group differences for any of the secondary endpoints. Peak cough frequency was low and occurred later in the study than expected (days 4-5). The safety profile was consistent with that of previous studies of gefapixant.ConclusionCompared with placebo, gefapixant did not reduce the frequency or severity of acute cough secondary to induced URTI. Induced viral URTI produced mild symptoms, including lower cough frequency than observed in previous studies of patients selected for acute cough associated with naturally occurring URTI.Trial registrationClinicalTrials.gov, NCT03569033; EudraCT, 2017-000472-28; protocol number, MK-7264-013.

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P2X3-selective mechanism of Gefapixant, a drug candidate for the treatment of refractory chronic cough.

Publications

P2X3-selective mechanism of Gefapixant, a drug candidate for the treatment of refractory chronic cough.

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