Molecular dynamic simulation reveals E484K mutation enhances spike RBD-ACE2 affinity and the combination of E484K, K417N and N501Y mutations (501Y.V2 variant) induces conformational change greater than N501Y mutant alone, potentially resulting in an escape mutant (preprint)

Rapidly spreading SARS-CoV-2 variants present not only an increased threat to human health due to the confirmed greater transmissibility of several of these new strains but, due to conformational changes induced by the mutations, may render first-wave SARS-CoV-2 convalescent sera, vaccine-induced antibodies, or recombinant neutralizing antibodies (nAbs) ineffective. To be able to assess the risk of viral escape from neutralization by first-wave antibodies, we leveraged our capability for Molecular Dynamic (MD) simulation of the spike receptor binding domain (S RBD) and its binding to human angiotensin-converting enzyme 2 (hACE2) to predict alterations in molecular interactions resulting from the presence of the E484K, K417N, and N501Y variants found in the South African 501Y.V2 strain - alone and in combination. We report here the combination of E484K, K417N and N501Y results in the highest degree of conformational alterations of S RBD when bound to hACE2, compared to either E484K or N501Y alone. Both E484K and N501Y increase affinity of S RBD for hACE2 and E484K in particular switches the charge on the flexible loop region of RBD which leads to the formation of novel favorable contacts. Enhanced affinity of S RBD for hACE2 very likely underpins the greater transmissibility conferred by the presence of either E484K or N501Y; while the induction of conformational changes may provide an explanation for evidence that the 501Y.V2 variant, distinguished from the B.1.1.7 UK variant by the presence of E484K, is able to escape neutralization by existing first-wave anti-SARS-CoV-2 antibodies and re-infect COVID-19 convalescent individuals.

A rapid phenomics workflow for the in vitro identification of antiviral drugs (preprint)

Morphological profiling of cells in the presence of perturbants, also known as phenomics, is gaining momentum given its successful implementation for drug discovery and compound profiling. The current COVID-19 pandemic has fueled the search for new and fast methods to identify novel or repurposed therapeutic drugs. A popular method to identify antiviral drugs is the use of antibody-based immunofluorescence to visualise infected cells. However, this method lacks depth towards the effect of such drugs on the host cells. Here we present a phenomics workflow for untargeted phenotypic drug screening of virus infected cells, combining Cell Painting with antibody-based detection of viral infection in a single and simple method and provide a semi-automated image analysis pipeline for classification and feature extraction of virus infected cells. Our phenomics workflow provides valuable information about the effect of both virus and drugs on the host cells. We validated our method using a panel of 9 antiviral compounds including known and novel compounds on MRC5 human lung fibroblasts infected with Human coronavirus 229E (CoV-229E). Two of the compounds showed strong antiviral efficacy concomitant with a recovery of the morphological profile towards non-infected.

Phylogenetic analyses of SARS-CoV-2 B.1.1.7 lineage suggest a single origin followed by multiple exportation events versus convergent evolution (preprint)

The emergence of new variants of SARS-CoV-2 herald a new phase of the pandemic. This study used state-of-the-art phylodynamic methods to ascertain that the rapid rise of B.1.1.7 "Variant of Concern" most likely occurred by global dispersal rather than convergent evolution from multiple sources.