Knowledge-based repositioning of the anti-HCV direct antiviral agent Sofosbuvir as SARS-CoV-2 treatment.
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ABSTRACT:
SUBMITTER: Buonaguro L
PROVIDER: S-EPMC7215134 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Coronavirus diseases 2019 (COVID-19) are seriously affecting human health all over the world. Nucleotide inhibitors have promising results in terms of its efficacy against different viral polymerases. In this study, detailed molecular docking and dynamics simulations are used to evaluate the binding affinity of a clinically approved drug, sofosbuvir, with the solved structure of the viral protein RNA-dependent RNA polymerase (RdRp) and compare it to the clinically approved drug, Remdesivir. These drugs are docked onto the three-dimensional structure of the nsp12 protein of SARS-CoV-2, which controls the polymerization process. Hence, it is considered one of the primary therapeutic targets for coronaviruses. Sofosbuvir is a drug that is currently used for HCV treatment; therefore, HCV RdRp is used as a positive control protein target. The protein dynamics are simulated for 100 ns, while the binding is tested during different dynamics states of the SARS-CoV-2 RdRp. Additionally, the drug-protein complexes are further simulated for 20 ns to explore the binding mechanism. The interaction of SARS-CoV-2 RdRp as a target with the active form of sofosbuvir as a ligand demonstrates binding effectiveness. One of the FDA-approved antiviral drugs, such as sofosbuvir, can help us in this mission, aiming to limit the danger of COVID-19. Sofosbuvir was found to bind nsp12 with comparable binding energies to that of Remdesivir, which has been reported for its potential against COVID-19 RdRp and is currently approved by the FDA.
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Project description:Ledipasvir, a direct acting antiviral agent (DAA) targeting the Hepatitis C Virus NS5A protein, exhibits picomolar activity in replicon cells. While its mechanism of action is unclear, mutations that confer resistance to ledipasvir in HCV replicon cells are located in NS5A, suggesting that NS5A is the direct target of ledipasvir. To date co-precipitation and cross-linking experiments in replicon or NS5A transfected cells have not conclusively shown a direct, specific interaction between NS5A and ledipasvir. Using recombinant, full length NS5A, we show that ledipasvir binds directly, with high affinity and specificity, to NS5A. Ledipasvir binding to recombinant NS5A is saturable with a dissociation constant in the low nanomolar range. A mutant form of NS5A (Y93H) that confers resistance to ledipasvir shows diminished binding to ledipasvir. The current study shows that ledipasvir inhibits NS5A through direct binding and that resistance to ledipasvir is the result of a reduction in binding affinity to NS5A mutants.
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Project description:Background:Hepatitis C virus (HCV) direct-acting antiviral therapy is effective among people receiving opioid substitution therapy (OST), but studies are limited by small numbers of nongenotype 1 (GT1) patients. The aim of this study was to evaluate the treatment completion, adherence, SVR12, and safety of sofosbuvir-based therapies in HCV patients receiving and not receiving OST. Methods:Ten phase 3 studies of sofosbuvir-based regimens included ION (ledipasvir/sofosbuvir ± ribavirin for 8, 12, or 24 weeks in GT1), ASTRAL (sofosbuvir/velpatasvir for 12 weeks in GT1-6), and POLARIS (sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir in GT1-6). Patients with clinically significant drug use (last 12 months) or noncannabinoids detected at screening were ineligible. Results:Among 4743 patients, 4% (n = 194) were receiving OST (methadone; n = 113; buprenorphine, n = 75; other, n = 6). Compared with those not receiving OST (n = 4549), those receiving OST (n = 194) were younger (mean age, 48 vs 54), more often male (73% vs 61%), GT3 (38% vs 17%), treatment-naïve (78% vs 65%), and cirrhotic (36% vs 23%). Among those receiving and not receiving OST, there was no significant difference in treatment completion (97% vs 99%, P = .06), SVR12 (94% vs 97%, P = .06), relapse (0.5% vs 2.1%, P = .19), adverse events (78% vs 77%, P = .79), or serious adverse events (3.6% vs 2.4%, P = .24). There was no difference in SVR12 in patients with cirrhosis (99% vs 95%, P = .25) or those with G3 (95% vs 95%, P = .77) in those receiving OST. Among patients receiving OST, SVR12 was high among those receiving methadone (95%) and buprenorphine (96%). Conclusion:Sofosbuvir-based therapies are effective and safe in patients receiving OST.
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Project description:Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly resulted in a global pandemic with approximately 4 million deaths. Effective oral antiviral agents are urgently needed to treat coronavirus disease-2019 (COVID-19), block SARS-CoV-2 transmission, and prevent progression to severe illness. Molnupiravir (formerly EIDD-2801), a prodrug of beta-d-N4-hydroxycytidine (EIDD-1931) and an inhibitor of RNA-dependent RNA polymerase, possesses significant activity against SARS-CoV-2. Its prophylactic efficacy has been evidenced in a ferret model. Two phase-I trials (NCT04392219 and NCT04746183) have demonstrated that oral molnupiravir is safe and well-tolerated at therapeutic doses. After five-days of oral molnupiravir therapy, satisfactory efficacies, assessed by eliminating nasopharyngeal virus in patients with early and mild COVID-19, were disclosed in two phase-II trials (NCT04405739 and NCT04405570). Two phase-II/III trials, NCT04575597 and NCT04575584, with estimated enrollments of 1850 and 304 cases, respectively, are ongoing. The NCT04575597 recently released that molnupiravir significantly reduced the risk of hospitalization or death in adults experiencing mild or moderate COVID-19. To benefit individual and public health, clinical applications of molnupiravir to promptly treat COVID-19 patients and prevent SARS-CoV-2 transmission may be expected.
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Project description:Dysregulated immune responses contribute to the excessive and uncontrolled inflammation observed in severe COVID-19. However, how immunity to SARS-CoV-2 is induced and regulated remains unclear. Here we uncover a role of the complement system in the induction of innate and adaptive immunity to SARS-CoV-2. Complement rapidly opsonizes SARS-CoV-2 particles via the lectin pathway. Complement-opsonized SARS-CoV-2 efficiently induces type-I interferon and pro-inflammatory cytokine responses via activation of dendritic cells, which are inhibited by antibodies against the complement receptors (CR) 3 and 4. Serum from COVID-19 patients, or monoclonal antibodies against SARS-CoV-2, attenuate innate and adaptive immunity induced by complement-opsonized SARS-CoV-2. Blocking of CD32, the FcγRII antibody receptor of dendritic cells, restores complement-induced immunity. These results suggest that opsonization of SARS-CoV-2 by complement is involved in the induction of innate and adaptive immunity to SARS-CoV-2 in the acute phase of infection. Subsequent antibody responses limit inflammation and restore immune homeostasis. These findings suggest that dysregulation of the complement system and FcγRII signaling may contribute to severe COVID-19.
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Project description:The optimal retreatment strategy for chronic hepatitis C virus (HCV) patients who fail directly-acting antiviral agent (DAA)-based treatment is unknown. In this study, we assessed the efficacy and safety of ledipasvir (LDV) and sofosbuvir (SOF) for 12 weeks in HCV genotype-1 (GT-1) patients who failed LDV/SOF-containing therapy.In this single-center, open-label, phase 2a trial, 34 participants with HCV (GT-1) and early-stage liver fibrosis who previously failed 4-6 weeks of LDV/SOF with GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks. The primary endpoint was HCV viral load below the lower limit of quantification 12 weeks after completion of therapy (sustained virological response [SVR]12). Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial relapse, prior to retreatment, and at second relapse with Illumina next-generation sequencing technology.Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 × 10(6) IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85%) had NS5A-resistant variants. The SVR12 rate was 91% (31/34; intention to treat, ITT) after retreatment. One patient relapsed.In patients who previously failed short-course combination DAA therapy, we demonstrate a high SVR rate in response to 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants.NCT01805882.
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