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Multi-target direct-acting SARS-CoV-2 antivirals against the nucleotide-binding pockets of virus-specific proteins.

ABSTRACT: The nucleotide-binding pockets (NBPs) in virus-specific proteins have proven to be the most successful antiviral targets for several viral diseases. Functionally important NBPs are found in various structural and non-structural proteins of SARS-CoV-2. In this study, the first successful multi-targeting attempt to identify effective antivirals has been made against NBPs in nsp12, nsp13, nsp14, nsp15, nsp16, and nucleocapsid (N) proteins of SARS-CoV-2. A structure-based drug repurposing in silico screening approach with ADME analysis identified small molecules targeting NBPs in SARS-CoV-2 proteins. Further, isothermal titration calorimetry (ITC) experiments validated the binding of top hit molecules to the purified N-protein. Importantly, cell-based antiviral assays revealed antiviral potency for INCB28060, darglitazone, and columbianadin with EC₅₀ values 15.71 μM, 5.36 μM, and 22.52 μM, respectively. These effective antivirals targeting multiple proteins are envisioned to direct the development of antiviral therapy against SARS-CoV-2 and its emerging variants.

SUBMITTER: Rani R

PROVIDER: S-EPMC9539459 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Multi-target direct-acting SARS-CoV-2 antivirals against the nucleotide-binding pockets of virus-specific proteins.

Rani Ruchi R Long Siwen S Pareek Akshay A Dhaka Preeti P Singh Ankur A Kumar Pravindra P McInerney Gerald G Tomar Shailly S

Virology 20221007

The nucleotide-binding pockets (NBPs) in virus-specific proteins have proven to be the most successful antiviral targets for several viral diseases. Functionally important NBPs are found in various structural and non-structural proteins of SARS-CoV-2. In this study, the first successful multi-targeting attempt to identify effective antivirals has been made against NBPs in nsp12, nsp13, nsp14, nsp15, nsp16, and nucleocapsid (N) proteins of SARS-CoV-2. A structure-based drug repurposing in silico ...[more]

PMID: 36244310

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Project description:BackgroundThe prevalence and risk factors for non-adherence to direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) in clinical practice settings are under-studied.Objectives(1) To quantify DAA non-adherence in the total cohort and among subgroups with and without mental health conditions, alcohol use, and substance use, and (2) to investigate patient- and treatment-level risk factor non-adherence.DesignProspective, observational cohort study.ParticipantsA total of 1562 patients receiving DAAs between January 2016 and October 2017 at 11 US medical centers including academic and community practices.Main measuresSelf-reported medication non-adherence, defined as any missed doses in the past 7 days, surveyed early (T2: at 4 ± 2 weeks) and late in treatment (T3: 2-3 weeks prior to end of treatment). Non-adherence to post-treatment follow-up visits was defined as absence of lab results after DAA therapy completion.Key resultsOf 1447 patients, 162 (11%) reported non-adherence at T2 or T3. Medical records indicated 262 (17%) of the 1562 participants had not returned for post-treatment visits. At baseline, 37% of patients reported mental health conditions, 15% reported alcohol use, and 23% reported using substances in the previous year. Baseline characteristics associated with DAA non-adherence included alcohol use (OR 1.96), younger age (< 35 years vs. > 55 years: OR 3.40), non-white race (OR > 2.26), and DAA treatment cohort, but not substance use or mental health condition. Non-adherence to follow-up exhibited association with younger age and a higher baseline overall symptom burden. Among 1287 patients with evaluable sustained virologic response (SVR) data, 53 patients (4%) did not achieve SVR. The bivariate correlation between adherence and SVR was negligible (r = 0.01).ConclusionsDAA non-adherence was low and SVR rates were high. Mental health conditions, substance use, and alcohol use should not disqualify patients from DAA therapy. Patients with alcohol use disorder before DAA therapy initiation may benefit from targeted on-treatment support.

Dataset Information

Multi-target direct-acting SARS-CoV-2 antivirals against the nucleotide-binding pockets of virus-specific proteins.

Publications

Multi-target direct-acting SARS-CoV-2 antivirals against the nucleotide-binding pockets of virus-specific proteins.

Similar Datasets

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