Genetic Study of SARS-CoV-2 Non Structural Protein 12 in COVID-19 Patients Non Responders to Remdesivir

Bravo, Marta Santos; Alonso, Rodrigo; Soria, Dafne; Palomino, Sonsoles Sánchez; Machuca, Ángela Sanzo; Rodrı́guez, Cristina; Alcamı́, José; Díez-Fuertes, Francisco; Redon, Àlvar Simarro; Hurtado, Juan Carlos; Avilés, Francesc Fernández; Bodro, Marta; Rubio, Elisa; Villanueva, José Luis Güell; Vergara, Andrea; Castro, Pedro; Tuset, Montserrat; Cuesta, G.; Puerta, Pedro; García, Carolina Soledad Romero; Gutiérrez, María Del Mar Mosquera; Martínez-Priego, Llúcia; Vila, Jordi; Soriano, Álex; Marcos, María Ángeles

doi:10.1128/spectrum.02448-22

Cited by 2 publications

(2 citation statements)

References 20 publications

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“…All of the patients were treated with the RdRp inhibitor remdesivir, and, interestingly, it turned out that the patients bearing the concomitant mutations P323L-G671S-M899I (3M 2 ) and P323L-G671S-L838I-D738Y-K91E (5M) in the RdRp machinery of SARS-CoV-2 showed a delayed or up to no response to remdesivir, which suggests that the progressive enrichment of mutations in RdRp can play a role in jeopardizing remdesivir efficacy, thereby promoting the onset of drug resistance. In keeping with our findings, another previous study supported the association of mutational patterns, including L838I, that are present at the remdesivir baseline, with a reduced or no response to the drug in vivo [ 37 ]. On the contrary, no relevant differences with respect to the P323L alone or the WT were observed in the remaining concomitant mutations pattern.…”

Section: Discussionsupporting

confidence: 92%

Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients

Gratteri,

Ambrosio,

Lupia

et al. 2023

Pharmaceuticals

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(1) Background: SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target to fight COVID-19, and many RdRp inhibitors nucleotide/nucleoside analogs, such as remdesivir, have been identified or are in clinical studies. However, the appearance of resistant mutations could reduce their efficacy. In the present work, we structurally evaluated the impact of RdRp mutations found at baseline in 39 patients treated with remdesivir and associated with a different degree of antiviral response in vivo. (2) Methods: A refined bioinformatics approach was applied to assign SARS-CoV-2 clade and lineage, and to define RdRp mutational profiles. In line with such a method, the same mutations were built and analyzed by combining docking and thermodynamics evaluations with both molecular dynamics and representative pharmacophore models. (3) Results: Clinical studies revealed that patients bearing the most prevalent triple mutant P323L+671S+M899I, which was present in 41% of patients, or the more complex mutational profile P323L+G671S+L838I+D738Y+K91E, which was found with a prevalence of 2.6%, showed a delayed reduced response to remdesivir, as confirmed by the increase in SARS-CoV-2 viral load and by a reduced theoretical binding affinity versus RdRp (ΔGbindWT = −122.70 kcal/mol; ΔGbindP323L+671S+M899I = −84.78 kcal/mol; ΔGbindP323L+G671S+L838I+D738Y+K91E = −96.74 kcal/mol). Combined computational approaches helped to rationalize such clinical observations, offering a mechanistic understanding of the allosteric effects of mutants on the global motions of the viral RNA synthesis machine and in the changes of the interactions patterns of remdesivir during its binding.

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Section: Discussionsupporting

confidence: 92%

Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients

Gratteri,

Ambrosio,

Lupia

et al. 2023

Pharmaceuticals

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“…Only one patient developed a rare Nsp12 substitution with diminished viral fitness that was associated with reduced in vitro susceptibility to remdesivir, indicating a high barrier to resistance [ 14 ]. In another study, no significant viral mutations were associated with remdesivir treatment failure in patients with severe COVID-19, except for the de novo E83D mutation, which emerged in an immunosuppressed patient after 18 days of treatment [ 15 ]. Real-world studies (Sect.…”

Section: Pharmacodynamic Properties Of Remdesivirmentioning

confidence: 99%

Remdesivir: A Review in COVID-19

Blair

2023

Drugs

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Remdesivir (Veklury ® ), a nucleotide analogue prodrug with broad-spectrum antiviral activity, is approved for the treatment of coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus 2 infection. Unlike some antivirals, remdesivir has a low potential for drug-drug interactions. In the pivotal ACTT-1 trial in hospitalized patients with COVID-19, daily intravenous infusions of remdesivir significantly reduced time to recovery relative to placebo. Subsequent trials provided additional support for the efficacy of remdesivir in hospitalized patients with moderate or severe COVID-19, with a greater benefit seen in patients with minimal oxygen requirements at baseline. Clinical trials also demonstrated the efficacy of remdesivir in other patient populations, including outpatients at high risk for progression to severe COVID-19, as well as hospitalized paediatric patients. In terms of mortality, results were equivocal. However, remdesivir appeared to have a small mortality benefit in hospitalized patients who were not already being ventilated at baseline. Remdesivir was generally well tolerated in clinical trials, but pharmacovigilance data found an increased risk of hepatic, renal and cardiovascular adverse drug reactions in the real-world setting. In conclusion, remdesivir represents a useful treatment option for patients with COVID-19, particularly those who require supplemental oxygen. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-023-01926-0.

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Genetic Study of SARS-CoV-2 Non Structural Protein 12 in COVID-19 Patients Non Responders to Remdesivir

Cited by 2 publications

References 20 publications

Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients

Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients

Remdesivir: A Review in COVID-19

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