Conserved coronavirus proteins as targets of broad-spectrum antivirals

Melo-Filho, Cleber C.; Bobrowski, Tesia; Martin, Holli-Joi; Sessions, Zoe; Popov, Konstantin; Moorman, Nathaniel J.; Baric, Ralph S.; Muratov, Eugene; Tropsha, Alexander

doi:10.1016/j.antiviral.2022.105360

Cited by 22 publications

(23 citation statements)

References 95 publications

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Section: Resultsmentioning

confidence: 99%

“…Beyond drug repurposing, another intuitive approach used in the most recent SARS-CoV-2 pandemic to identify BSA drugs across the coronaviruses was through identifying proteome conservation, which was studied by Schapira et al 31 as well as our group. 3 Schapira et al analyzed the conservation of all available PDB structures of α- and β-coronaviruses, as well as samples from patients with SARS-CoV-2 by mapping druggable binding pockets onto experimental structures of SARS-CoV-2 proteins. Our work complemented that of Schapira et al, 31 by exploring the idea that similarities between homologous coronaviral proteins could be exploited for target selection and the development of broad-spectrum anti-coronaviral compounds.…”

Section: Discussionmentioning

confidence: 99%

“…In these cases, we could suggest the compound be tested against the same target in the untested yet highly homologous viruses from the same family, using the principle of viral protein conservation. 3 There were also instances of compounds, such as CHEMBL267099 (tubercidin), reported active in a phenotypic assay for a virus in one family (HPIV-3) and active in a target-based assay of another (Zika NS5 protein). Cases like these are particularly interesting, because after making this connection one can suggest testing this compound in various HPIV-3 targets, live cell Zika virus, as well as the other highly homologous Flaviviridae members (West Nile, Yellow Fever, Dengue) in live cell assay and against the NS5 protein.…”

Section: Concordance Between the Phenotypic And Target-based Datamentioning

confidence: 99%

“…2 The millions of lives lost and trillions of dollars in damage to the global economy due to the recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlight the importance of medications that can offer protection against diverse viral threats that can emerge in the future. 3 It is evident from the current SARS-CoV-2 outbreak that scientific advances have increased our capabilities for rapid development of new vaccines. However, none of the vaccines developed thus far offers 100% protection.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Small Molecule Antiviral Compound Collection (SMACC): a database to support the discovery of broad-spectrum antiviral drug molecules

Martin

Melo-Filho

Korn

et al. 2022

Preprint

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Diseases caused by new viruses costs thousands if not millions of human lives and trillions of dollars in damage to the global economy. Despite the rapid development of vaccines for SARS-CoV-2, the lack of small molecule antiviral drugs that work against multiple viral families (broad-spectrum antivirals; BSAs) has left the entire world human population vulnerable to the infection between the beginning of the outbreak and the widespread availability of vaccines. Developing BSAs is an attractive, yet challenging, approach that could prevent the next, inevitable, viral outbreak from becoming a global catastrophe. To explore whether historical medicinal chemistry efforts suggest the possibility of discovering novel BSAs, we (i) identified, collected, curated, and integrated all chemical bioactivity data available in ChEMBL for molecules tested in respective assays for 13 emerging viruses that, based on published literature, hold the greatest potential threat to global human health; (ii) identified and solved the challenges related to data annotation accuracy including assay description ambiguity, missing cell or target information, and incorrect BioAssay Ontology (BAO) annotations; (iii) developed a highly curated and thoroughly annotated database of compounds tested in both phenotypic (21,392 entries) and target-based (11,123 entries) assays for these viruses; and (iv) identified a subset of compounds showing BSA activity. For the latter task, we eliminated inconclusive and annotated duplicative entries by checking the concordance between multiple assay results and identified eight compounds active against 3-4 viruses from the phenotypic data, 16 compounds active against two viruses from the target-based data, and 35 compounds active in at least one phenotypic and one target-based assay. The pilot version of our SMACC (Small Molecule Antiviral Compound Collection) database contains over 32,500 entries for 13 viruses. Our analysis indicates that previous research yielded very small number of BSA compounds. We posit that focused and coordinated efforts strategically targeting the discovery of such agents must be established and maintained going forward. The SMACC database publicly available at https://smacc.mml.unc.edu may serve as a reference for virologists and medicinal chemists working on the development of novel BSA agents in preparation for future viral outbreaks.

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Section: Resultsmentioning

confidence: 99%