Abstract
Animal toxins present a major threat to human health worldwide, predominantly through snakebite envenomings, which are responsible for over 100,000 deaths each year. To date, the only available treatment against snakebite envenoming is plasma-derived antivenom. However, despite being key to limiting morbidity and mortality among snakebite victims, current antivenoms suffer from several drawbacks, such as immunogenicity and high cost of production. Consequently, avenues for improving envenoming therapy, such as the discovery of toxin-sequestering monoclonal antibodies against medically important target toxins through phage display selection, are being explored. However, alternative binding protein scaffolds that exhibit certain advantages compared to the well-known immunoglobulin G scaffold, including high stability under harsh conditions and low cost of production, may pose as possible low-cost alternatives to antibody-based therapeutics. There is now a plethora of alternative binding protein scaffolds, ranging from antibody derivatives (e.g., nanobodies), through rationally designed derivatives of other human proteins (e.g., DARPins), to derivatives of non-human proteins (e.g., affibodies), all exhibiting different biochemical and pharmacokinetic profiles. Undeniably, the high level of engineerability and potentially low cost of production, associated with many alternative protein scaffolds, present an exciting possibility for the future of snakebite therapeutics and merit thorough investigation. In this review, a comprehensive overview of the different types of binding protein scaffolds is provided together with a discussion on their relevance as potential modalities for use as next-generation antivenoms.
Highlights
Animal toxins have troubled humankind for millennia
(>57,600 deaths per year) and sub-Saharan Africa (>32,100 deaths per year) and has been unequivocally associated with poverty [3]. This has led to its recent reclassification as a Neglected Tropical Disease (NTD) by the World Health Organization [4]
Affibodies, anticalins, and designed ankyrin repeat proteins (DARPins) among others, and are small, single-domain proteins that typically lack disulfide bonds, require no post-translational modifications, and can undergo straightforward multimerization (Figure 1) [25]. They present promising therapeutic scaffolds for antitoxin development, since their cost of production has the potential to be lower than the cost of production for Immunoglobulin G antibodies (IgGs), and since their high stability could render cold chain unnecessary in their geographical distribution, which is a significant advantage for envenomation treatment in rural areas where snakebite antivenom is needed the most [25]
Summary
Animal toxins have troubled humankind for millennia. These toxic proteins have evolved for use in prey subduction or as a natural defense mechanism to repel or kill predators by exerting. Affibodies, anticalins, and designed ankyrin repeat proteins (DARPins) among others, and are small, single-domain proteins that typically lack disulfide bonds, require no post-translational modifications, and can undergo straightforward multimerization (Figure 1) [25] They present promising therapeutic scaffolds for antitoxin development, since their cost of production has the potential to be lower than the cost of production for IgGs (e.g., through low-cost microbial expression), and since their high stability could render cold chain unnecessary in their geographical distribution, which is a significant advantage for envenomation treatment in rural areas where snakebite antivenom is needed the most [25]. We briefly assess the potential impact of the implementation of alternative protein scaffolds as therapeutic agents against envenomings
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