FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4319304326> ?p ?o ?g. }

• W4319304326 endingPage "5360" @default.
• W4319304326 startingPage "5349" @default.
• W4319304326 abstract "The human Betacoronavirus SARS-CoV-2 is a novel pathogen claiming millions of lives and causing a global pandemic that has disrupted international healthcare systems, economies, and communities. The virus is fast mutating and presenting more infectious but less lethal versions. Currently, some small-molecule therapeutics have received FDA emergency use authorization for the treatment of COVID-19, including Lagevrio (molnupiravir) and Paxlovid (nirmaltrevir/ritonavir), which target the RNA-dependent RNA polymerase and the 3CLpro main protease, respectively. Proteins downstream in the viral replication process, specifically the nonstructural proteins (Nsps1-16), are potential drug targets due to their crucial functions. Of these Nsps, Nsp4 is a particularly promising drug target due to its involvement in the SARS-CoV viral replication and double-membrane vesicle formation (mediated via interaction with Nsp3). Given the degree of sequence conservation of these two Nsps across the Betacoronavirus clade, their protein-protein interactions and functions are likely to be conserved as well in SARS-CoV-2. Through AlphaFold2 and its recent advancements, protein structures were generated of Nsp3 and 4 lumenal loops of interest. Then, using a combination of molecular docking suites and an existing library of lead-like compounds, we virtually screened 7 million ligands to identify five putative ligand inhibitors of Nsp4, which could present an alternative pharmaceutical approach against SARS-CoV-2. These ligands exhibit promising lead-like properties (ideal molecular weight and log P profiles), maintain fixed-Nsp4-ligand complexes in molecular dynamics (MD) simulations, and tightly associate with Nsp4 via hydrophobic interactions. Additionally, alternative peptide inhibitors based on Nsp3 were designed and shown in MD simulations to provide a highly stable binding to the Nsp4 protein. Finally, these therapeutics were attached to dendrimer structures to promote their multivalent binding with Nsp4, especially its large flexible luminal loop (Nsp4LLL). The therapeutics tested in this study represent many different approaches for targeting large flexible protein structures, especially those localized to the ER. This study is the first work targeting the membrane rearrangement system of viruses and will serve as a potential avenue for treating viruses with similar replicative function." @default.
• W4319304326 created "2023-02-07" @default.
• W4319304326 creator A5004297920 @default.
• W4319304326 creator A5018581192 @default.
• W4319304326 creator A5029247141 @default.
• W4319304326 creator A5038585213 @default.
• W4319304326 creator A5044620273 @default.
• W4319304326 creator A5061348580 @default.
• W4319304326 creator A5065545218 @default.
• W4319304326 creator A5074102781 @default.
• W4319304326 creator A5077173021 @default.
• W4319304326 creator A5083693551 @default.
• W4319304326 creator A5086039900 @default.
• W4319304326 date "2023-02-06" @default.
• W4319304326 modified "2023-10-10" @default.
• W4319304326 title "Scalable Inhibitors of the Nsp3–Nsp4 Coupling in SARS-CoV-2" @default.
• W4319304326 cites W1757990252 @default.
• W4319304326 cites W1887624773 @default.
• W4319304326 cites W1968991415 @default.
• W4319304326 cites W1981491253 @default.
• W4319304326 cites W2004837736 @default.
• W4319304326 cites W2015458396 @default.
• W4319304326 cites W2024124160 @default.
• W4319304326 cites W2025816743 @default.
• W4319304326 cites W2029667189 @default.
• W4319304326 cites W2030433671 @default.
• W4319304326 cites W2055043387 @default.
• W4319304326 cites W2064885619 @default.
• W4319304326 cites W2067054452 @default.
• W4319304326 cites W2067174909 @default.
• W4319304326 cites W2070753604 @default.
• W4319304326 cites W2072952339 @default.
• W4319304326 cites W2080245527 @default.
• W4319304326 cites W2092581586 @default.
• W4319304326 cites W2105466816 @default.
• W4319304326 cites W2105668062 @default.
• W4319304326 cites W2111564907 @default.
• W4319304326 cites W2134967712 @default.
• W4319304326 cites W2135732933 @default.
• W4319304326 cites W2142748199 @default.
• W4319304326 cites W2150853746 @default.
• W4319304326 cites W2169678694 @default.
• W4319304326 cites W2170492999 @default.
• W4319304326 cites W2194379514 @default.
• W4319304326 cites W2206954826 @default.
• W4319304326 cites W2327533467 @default.
• W4319304326 cites W2564509927 @default.
• W4319304326 cites W2572080171 @default.
• W4319304326 cites W2738380970 @default.
• W4319304326 cites W2768064447 @default.
• W4319304326 cites W2772606519 @default.
• W4319304326 cites W2796891927 @default.
• W4319304326 cites W2819403710 @default.
• W4319304326 cites W2908023298 @default.
• W4319304326 cites W2968494487 @default.
• W4319304326 cites W2976040872 @default.
• W4319304326 cites W2987451562 @default.
• W4319304326 cites W2999364275 @default.
• W4319304326 cites W3000251091 @default.
• W4319304326 cites W3003217347 @default.
• W4319304326 cites W3003464757 @default.
• W4319304326 cites W3003639008 @default.
• W4319304326 cites W3011134208 @default.
• W4319304326 cites W3014067025 @default.
• W4319304326 cites W3034852029 @default.
• W4319304326 cites W3045802278 @default.
• W4319304326 cites W3045822005 @default.
• W4319304326 cites W3046751266 @default.
• W4319304326 cites W3047439400 @default.
• W4319304326 cites W3087343895 @default.
• W4319304326 cites W3088914369 @default.
• W4319304326 cites W3092775354 @default.
• W4319304326 cites W3114047206 @default.
• W4319304326 cites W3124360307 @default.
• W4319304326 cites W3134956475 @default.
• W4319304326 cites W3164046276 @default.
• W4319304326 cites W3172248163 @default.
• W4319304326 cites W3173623385 @default.
• W4319304326 cites W3177200467 @default.
• W4319304326 cites W3177353388 @default.
• W4319304326 cites W3177828909 @default.
• W4319304326 cites W3179206042 @default.
• W4319304326 cites W3182094313 @default.
• W4319304326 cites W3182882252 @default.
• W4319304326 cites W3183475563 @default.
• W4319304326 cites W3184226105 @default.
• W4319304326 cites W3191826804 @default.
• W4319304326 cites W3200679256 @default.
• W4319304326 cites W3201299379 @default.
• W4319304326 cites W3214213915 @default.
• W4319304326 cites W4205172550 @default.
• W4319304326 cites W4206563428 @default.
• W4319304326 cites W4226076101 @default.
• W4319304326 doi "https://doi.org/10.1021/acsomega.2c06384" @default.
• W4319304326 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36798146" @default.
• W4319304326 hasPublicationYear "2023" @default.
• W4319304326 type Work @default.
• W4319304326 citedByCount "0" @default.

• next