Recent Advances in Next Generation Snakebite Antivenoms

Abstract

With the inclusion of snakebite envenoming on the World Health Organization’s list of Neglected Tropical Diseases, an incentive has been established to promote research and development effort in novel snakebite antivenom therapies. Various technological approaches are being pursued by different research groups, including the use of small molecule inhibitors against enzymatic toxins as well as peptide- and oligonucleotide-based aptamers and antibody-based biotherapeutics against both enzymatic and non-enzymatic toxins. In this article, the most recent advances in these fields are presented, and the advantages, disadvantages, and feasibility of using different toxin-neutralizing molecules are reviewed. Particular focus within small molecules is directed towards the inhibitors varespladib, batimastat, and marimastat, while in the field of antibody-based therapies, novel recombinant polyclonal plantivenom technology is discussed.

High throughput screening and identification of coagulopathic snake venom proteins and peptides using nanofractionation and proteomics approaches

“…This process results in only 10-20% of antibodies being specific to venom toxins, with the remainder directed against environmental antigens, and of those specific antibodies only a proportion will actually be specific to the key pathogenic toxins found in any particular venom [88]. Thus, much research effort is now focusing upon increasing the specificity of therapies to specific, pathogenically-important, venom toxins, including the novel application of small molecule inhibitors and monoclonal antibodies [89][90][91][92][93][94]. For both these approaches, screening and identification platforms are important for the selection of molecules exhibiting desirable in vitro neutralizing profiles from large drug or antibodies libraries.…”

Repurposing Cancer Drugs Batimastat and Marimastat to Inhibit the Activity of a Group I Metalloprotease from the Venom of the Western Diamondback Rattlesnake, Crotalus atrox

“…SVMPs are involved in a wide range of toxic activities, including the degradation of collagen and other basement membrane components, fibrinogen and a range of other proteins [13]. The peptidomimetic molecules, batimastat and marimastat are broad-spectrum matrix metalloprotease (MMPs) inhibitors [16] that have been proposed as next generation treatment options for the SVMP-induced effects of SBE [17]. This inhibition is achieved by mimicking the cleavage site of natural substrates and binding to the zinc ion found in the active site of these proteases.…”

Screening of Antigen-Specific Antibody-Secreting Cells

“…While successful in preventing and curing disease, these treatments often induced anaphylactic reactions, also known as serum sickness, now known to be due to a hyperimmune response to the foreign animal serum proteins. However, many effective antisera remain in use, including antivenoms (Knudsen and Laustsen 2018) and products against bacterial toxins (diphtheria, tetanus, botulinum) and against viruses (rabies, hepatitis B, varicella zoster, vaccinia, cytomegalovirus) (Graham and Ambrosino 2015). With the discovery of antibodies as the agents responsible for the efficacy of immune sera, coupled with technology to isolate and produce mAbs, mAbs have emerged as promising therapeutics without the toxic side effects of whole serum transfer.…”