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Assessing Target Specificity of the Small Molecule Inhibitor Marimastat to Snake Venom Toxins: A Novel Application of Thermal Proteome Profiling

ABSTRACT: New treatments that circumvent the pitfalls of traditional antivenom therapies are critical to address the problem of snakebite globally. Numerous snake venom toxin inhibitors have shown promising cross-species neutralization of medically significant venom toxins in vivo and in vitro. The development of high-throughput approaches for the screening of such inhibitors could accelerate their identification, testing, and implementation, and thus holds exciting potential for improving the treatments and outcomes of snakebite envenomation worldwide. Energetics-based proteomic approaches, including Thermal Proteome Profiling (TPP) and Proteome Integral Solubility Alteration (PISA), assays represent “deep proteomics” methods for high throughput, proteome-wide identification of drug targets and ligands. In the following study, we apply TPP and PISA methods to characterize the interactions between venom toxin proteoforms in Crotalus atrox (Western Diamondback Rattlesnake) and the snake venom metalloprotease (SVMP) inhibitor marimastat. We investigate its venom proteome-wide effects and characterize its interactions with specific SVMP proteoforms, as well as its potential targeting of non-SVMP venom toxin families. We also compare the performance of PISA thermal window and soluble supernatant with insoluble precipitate using two inhibitor concentrations, providing the first demonstration of the utility of a sensitive high-throughput PISA-based approach to assess the direct targets of small molecule inhibitors for snake venom.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Crotalus Atrox

TISSUE(S): Venom

SUBMITTER: Anthony Saviola

LAB HEAD: Anthony Saviola

PROVIDER: PXD046399 | Pride | 2024-06-22

REPOSITORIES: Pride

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Assessing Target Specificity of the Small Molecule Inhibitor MARIMASTAT to Snake Venom Toxins: A Novel Application of Thermal Proteome Profiling.

Smith Cara F CF Modahl Cassandra M CM Ceja Galindo David D Larson Keira Y KY Maroney Sean P SP Bahrabadi Lilyrose L Brandehoff Nicklaus P NP Perry Blair W BW McCabe Maxwell C MC Petras Daniel D Lomonte Bruno B Calvete Juan J JJ Castoe Todd A TA Mackessy Stephen P SP Hansen Kirk C KC Saviola Anthony J AJ

Molecular & cellular proteomics : MCP 20240427 6

New treatments that circumvent the pitfalls of traditional antivenom therapies are critical to address the problem of snakebite globally. Numerous snake venom toxin inhibitors have shown promising cross-species neutralization of medically significant venom toxins in vivo and in vitro. The development of high-throughput approaches for the screening of such inhibitors could accelerate their identification, testing, and implementation and thus holds exciting potential for improving the treatments a ...[more]

PMID: 38679388

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Project description:Snake venoms have evolved in a few families of Caenophidae, and their toxins have been fine-tuned over the evolutive process into highly effective biochemical weapons with a particular role as a trophic adaptation. However, there are many outstanding questions on how venom contributes to the success of venomous species and their adaptation to different environments. Here we analyze the venoms from sympatric and generalist specimens of B. hyoprora, B. taeniatus, B. b. smaragdinus, B. brazili, and B. atrox collected in the wild of Alto Juruá region at the Amazon Forest aiming to understand whether the venom composition could be a driver or influence the arboreal habitats of B. taeniatus and B. b. smaragdinus, or the successful dispersion of B. atrox across the Amazon Forest. Venom composition and the primary sequences of toxin isoforms were characterized by venom gland transcriptomics followed by proteomics. The venom composition of the five species conserved the same protein families present in venoms of Bothropoid snakes but with remarkable differences in the chromatographic profiles and in the relative amount of each toxin group: CTLs were the most abundant in the venoms of B. taeniatus (31.6%), B. b. smaragdinus (33.0%), and B. atrox (32.0%) and SVMPs and PLA2s dominated in venoms of B. hyoprora (23.7% and 20.2%) and B. brazili (20.2% and 20.4%). Some peculiarities were also observed: B. hyoprora venom was the least complex, conserving important isoforms shared with B. atrox venom; the presence of one cluster of SVSPs exclusive to B. brazili venom isoforms; and the presence of the K49-PLA2 homologs only in B. b. smaragdinus and particularly in B. brazili venoms. The SVMP, SVSP, and PLA2 enzyme activities were consistent with the abundance and type of isoforms present in the venoms. B. hyoprora, B. taeniatus, B. b. smaragdinus, and B. atrox venoms presented low lethality to small rodents, while B. brazili venom was the most lethal. Concluding, differences were evidenced between the venoms of B. taeniatus and B. b. smaragdinus arboreal species, while B. b. smaragdinus shared a venom with a similar composition to B. atrox venom, mostly terrestrial. Considering the role of venom toxicity in species' success for adaptation in different areas, B. atrox is the most adapted in the whole Amazonian territory and presented the least lethal venom, while the venom of B. brazili was the most lethal despite its small distribution in the same area. Therefore, our data suggest that the selection of venom composition may not influence the success or behavior of snake species. In this way, other biotic or abiotic factors influence their foraging status or their dispersal in different ecological niches.

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	AtroxTPP_37A.raw	Raw
	AtroxTPP_37B.raw	Raw
	AtroxTPP_40A.raw	Raw
	AtroxTPP_40B.raw	Raw
	AtroxTPP_45A.raw	Raw