Developing Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite

Abstract

The World Health Organization (WHO) recently added snakebite envenoming to the priority list of Neglected Tropical Diseases (NTD). It is thought that ~75% of mortality following snakebite occurs outside the hospital setting, making the temporal gap between a bite and antivenom administration a major therapeutic challenge. Small molecule therapeutics (SMTs) have been proposed as potential prereferral treatments for snakebite to help address this gap. Herein, we discuss the characteristics, potential uses, and development of SMTs as potential treatments for snakebite envenomation. We focus on SMTs that are secretory phospholipase A2 (sPLA₂) inhibitors with brief exploration of other potential drug targets on venom molecules.

Figure 1

Potential uses of an SMT, via PO (oral), or IV (intravenous).

Figure 2

Advantages and limitations of antivenom and SMTs. If proven effective, an SMT might address some limitations of antivenom and vice versa. (COGS = Cost of Goods).

Figure 3

Hypothetical pipeline of SMTs for snakebite treatment. (a) Targeted inhibition of major snake venom enzymatic toxins, secreted phospholipase A2 (sPLA₂), and metallo- and serine-proteases (svMP and SP), through a combination of multiple inhibitory small molecules. (b) In combination with biologicals or others as adjuncts to antivenom for hospital administration (e.g., for targeting non-enzymatic toxins, such as 3-FTX).

Figure 4

Hit to Lead: a variety of strategies to discover new SMTs and an example of processes and targets for High Throughput Screening (HTS) of candidate snake venom SMTs. sPLA₂, svMP, and SP serve as examples of potential targets. Different assay methods are used for each type of enzymatic activity so screens would be run separately even if compound libraries were the same.

Figure 5

Scheme of a potential SMT development pathway. “Sections” correspond to paragraphs that follow. The repurposing pathway accelerates development and lowers costs by starting at a more advanced stage of development than a new chemical entity.

Figure 6

Structure of candidate SMTs for repurposing: varespladib (top left), its orally bioavailable pro-drug, methyl-varespladib (top right), prinomastat (bottom left), and marimatsat (bottom right). Marimastat and prinomastat are both orally bioavailable and could be combined (mixed or copackaged) for more extensive coverage as field antidotes [1, 54].