“…Small proteins such as heavy-chain-only camelid antibodies (called VHHs, nanobodies, or single-domain antibodies) and de novo designed mini-proteins against the toxins are currently being developed as alternatives (Chevalier et al, 2017;Conway et al, 2010;Godakova et al, 2019;Mukherjee et al, 2012;Thanongsaksrikul et al, 2010). These small proteins have high stability, can be economically produced, display high binding affinity, and have been shown to function effectively as antitoxins in animal models (Dong et al, 2010;Herrera et al, 2015;Schmidt et al, 2016;Sheoran et al, 2015;Vance et al, 2013;Vrentas et al, 2016). However, the therapeutic applications of these antitoxins have been limited by a lack of understanding of the molecular mechanisms underlying BoNT neutralization, the extreme potency of BoNTs (in vivo lethal blood concentrations at sub-pM), as well as the diverse sequences among different BoNT serotypes and subtypes.…”