Comparative Analysis of Alpha-1 Orthosteric-Site Binding by a Clade of Central American Pit Vipers (Genera Atropoides, Cerrophidion, Metlapilcoatlus, and Porthidium)

Abstract

The distribution and relative potency of post-synaptic neurotoxic activity within Crotalinae venoms has been the subject of less investigation in comparison with Elapidae snake venoms. No previous studies have investigated post-synaptic neurotoxic activity within the Atropoides, Metlapilcoatlus, Cerrophidion, and Porthidium clade. Given the specificity of neurotoxins to relevant prey types, we aimed to uncover any activity present within this clade of snakes that may have been overlooked due to lower potency upon humans and thus not appearing as a clinical feature. Using biolayer interferometry, we assessed the relative binding of crude venoms to amphibian, lizard, bird, rodent and human α-1 nAChR orthosteric sites. We report potent alpha-1 orthosteric site binding in venoms from Atropoides picadoi, Metlapilcoatlus occiduus, M. olmec, M. mexicanus, M. nummifer. Lower levels of binding, but still notable, were evident for Cerrophidion godmani, C. tzotzilorum and C. wilsoni venoms. No activity was observed for Porthidium venoms, which is consistent with significant alpha-1 orthosteric site neurotoxicity being a trait that was amplified in the last common ancestor of Atropoides/Cerrophidion/Metlapilcoatlus subsequent to the split by Porthidium. We also observed potent taxon-selective activity, with strong selection for non-mammalian targets (amphibian, lizard, and bird). As these are poorly studied snakes, much of what is known about them is from clinical reports. The lack of affinity towards mammalian targets may explain the knowledge gap in neurotoxic activity within these species, since symptoms would not appear in bite reports. This study reports novel venom activity, which was previously unreported, indicating toxins that bind to post-synaptic receptors may be more widespread in pit vipers than previously considered. While these effects appear to not be clinically significant due to lineage-specific effects, they are of significant evolutionary novelty and of biodiscovery interest. This work sets the stage for future research directions, such as the use of in vitro and in vivo models to determine whether the alpha-1 orthosteric site binding observed within this study confers neurotoxic venom activity.

Potential Biotechnological Applications of Venoms from the Viperidae Family in Central America for Thrombosis

“…But their venoms are diverse [ 18 ], with a higher predominance of Zinc-dependent metalloproteinases (SVMPs) in the genus Atropoides and a higher predominance of phospholipases A 2 (PLA 2 s) in the venom of Metlapilcoatlus . Despite the importance of the genus in Costa Rica, characterization of the venom compounds still needs to be accomplished, and few studies have been focused on the venom’s coagulotoxic effect, regardless of the venom’s anti-thrombotic potential [ 48 ].…”

“…These PLA 2 s have demonstrated myotoxic action in vivo [ 70 ] and in vitro [ 56 ]. Additionally, the crude venom of C. godmani has anti-coagulant properties, as it can inhibit Factor Xa, XIa, and prothrombinase complex formation and exhibit fibrinogenolytic activity [ 48 , 66 ]. Furthermore, the venom of C. godmani can bind to α-1 nAChR orthosteric sites, indicating potential postsynaptic neurotoxicity with higher selectivity for non-mammalian targets [ 48 ].…”

“…Additionally, the crude venom of C. godmani has anti-coagulant properties, as it can inhibit Factor Xa, XIa, and prothrombinase complex formation and exhibit fibrinogenolytic activity [ 48 , 66 ]. Furthermore, the venom of C. godmani can bind to α-1 nAChR orthosteric sites, indicating potential postsynaptic neurotoxicity with higher selectivity for non-mammalian targets [ 48 ]. Interestingly, the RGD disintegrin sasaimin, isolated from the venom of C. sasai , has anti-platelet aggregation and endothelial cell adhesion properties [ 73 ], indicating that the venom of C. godmani may also contain promising disintegrins.…”

“…The venom composition of this genus majoritarily comprises SVMPs and SVSPs. Extraordinarily, the venom of M. mexicanus contains three-finger toxins (3FTx) [ 18 , 20 , 48 , 84 ]. Despite the potential and uniqueness of the venom of this genus, only a few studies have focused on purified venom compounds and their biotechnological potential [ 18 , 20 , 48 , 84 ].…”