(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 ( Delta Gbind(WT) = 122.70 kcal/mol; delta Gbind(P323L+ 671S+M899I) = 84.78 kcal/mol; delta Gbind(P323L+ 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.

Gratteri, C., Ambrosio, F.a., Lupia, A., Moraca, F., Catalanotti, B., Costa, G., et al. (2023). Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients. PHARMACEUTICALS, 16(8) [10.3390/ph16081143].

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

Bellocchi, Maria;Carioti, Luca;Salpini, Romina;Ceccherini-Silberstein, Francesca;Frazia, Simone La;Malagnino, Vincenzo;Sarmati, Loredana;Svicher, Valentina;Artese, Anna;
2023-08-12

Abstract

(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 ( Delta Gbind(WT) = 122.70 kcal/mol; delta Gbind(P323L+ 671S+M899I) = 84.78 kcal/mol; delta Gbind(P323L+ 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.
12-ago-2023
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/07
Settore MEDS-03/A - Microbiologia e microbiologia clinica
English
PCA
RNA-dependent RNA polymerase
SARS-CoV-2
molecular dynamics
mutations
pharmacophore
remdesivir
Gratteri, C., Ambrosio, F.a., Lupia, A., Moraca, F., Catalanotti, B., Costa, G., et al. (2023). Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients. PHARMACEUTICALS, 16(8) [10.3390/ph16081143].
Gratteri, C; Ambrosio, Fa; Lupia, A; Moraca, F; Catalanotti, B; Costa, G; Bellocchi, M; Carioti, L; Salpini, R; Ceccherini-Silberstein, F; Frazia, Sl;...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/356970
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