Expanding the watch list for potential Ebola virus antibody escape mutations

Abstract

The 2014 outbreak of Ebola virus (EBOV) in Western Africa is the largest recorded filovirus disease outbreak and lead to the death of over 11,000 people. This deadly virus still poses a grave epidemic threat as evidenced by the current (since May 2018) EBOV outbreak in the Democratic Republic of the Congo which has already claimed the lives of over 250 people. One important strategy for combating EBOV epidemics is to anticipate how the evolution of EBOV might undermine treatment since the development of vaccines and antibody therapies are typically based on a single strain (often the 1976 Mayinga) of the EBOV envelope glycoprotein (GP). In a previous study we initiated a watch list of potential antibody escape mutations of EBOV by modeling interactions between EBOV GP and the monoclonal antibody KZ52. This watch list was generated using molecular modeling to estimate the effect of every possible mutation of GP. The final watch list containing 34 mutations were predicted to disrupt GP-KZ52 binding but not to disrupt the ability of GP to fold and to form trimers. In this study, we expand our watch list by including three more monoclonal antibodies with distinct epitopes on GP, namely Antibody 100 (Ab100), Antibody 114 (Ab114) and 13F6-1-2. Our updated watch list contains 127 mutations, three of which have been seen in humans or are experimentally associated with reduced efficacy of antibody treatment. We believe mutations on this broad watch list require attention since they may be a signal of an evolutionary response from EBOV to treatment that could diminish the effectiveness of interventions.

Remdesivir targets a structurally analogous region of the Ebola virus and SARS-CoV-2 polymerases

“…While the F548 residue is completely conserved across known filoviruses, this may not be true for newly emergent sequences or for variants that arise amid ongoing outbreaks. As such variants may reduce the effectiveness of remdesivir, or of other mechanistically similar nucleotide analogs that may be in development, we suggest that substitutions at the polymerase F548 position, particularly F548S, be added alongside the watch list of antibody escape mutations in the EBOV glycoprotein (28,29) and be subject to particular attention during surveillance.…”

Predicting the viability of beta-lactamase: How folding and binding free energies correlate with beta-lactamase fitness

“…In the following, we term those simulations in which molecular dynamics relaxation was performed before FoldX free energies were computed MD+FoldX simulations. Past studies performed by our team have shown that relaxing the wild type structure before introducing mutations can significantly improve the predictive capacity of FoldX on proteins, such as TEM-1, on which FoldX was not explicitly trained [61,62]. In our MD+FoldX simulations, the final clean structure file was used to carry out atomistic molecular dynamics simulations using the protocol reported in our previous studies [61,62].…”

High resolution profiling of pathways of escape for SARS-CoV-2 spike-binding antibodies

“…Our results also demonstrate the power of interrogating the role of every possible amino acid at every site on the S protein. Mapping COVID-19 patient serum epitopes by alanine scanning has helped identify sites of antibody binding by removing important side chains interactions (Shrock et al, 2020), but studies with other viruses have shown that escape can be mediated by mutations at sites not directly in contact with the antibody via introduction of nearby charged or bulky amino acids (Dingens et al, 2019;Doud et al, 2017;Patel et al, 2019). This concept was evident in this study, for example within the FP epitope for patient 8, where addition of negatively charged amino acids led to escape at site S816 but addition of an alanine did not.…”