Coral snakes of the American continent are the most diverse group within the Elapidae family. They are represented by three genera, with Micrurus standing out due to its high number of species (∼83) and wide distribution, from the Southern United States to Argentina [1]. Coral snakes, in proportion to other snakes, cause fewer envenomations, estimated at approximately 3 % of snakebites in Latin America [2]. Although this may seem a small percentage, it is of great importance due to the high lethality of their venoms and the severe neurotoxic clinical syndrome they can cause [3]. In Mexico, the coral snakes of the genus Micrurus include 14 species, all with distinct coloration patterns; some species may even present intraspecific variation in coloration patterns [1]. A recent taxonomic study on coral snakes highlights the need for more research regarding the genus Micrurus to the extent that the number of species could change quickly [4]. Therefore, to account for this unresolved taxonomy, we believe that venom studies should always be accompanied by precise information on the collection site, and adequate storage of tissue samples, which should facilitate the tracking of taxonomic changes. In Mexico, an average of 3800 snakebites occur annually; however, the number of bites that vipers and elapids cause is unknown. Estimates suggest that coral snakes could account for 1 to 2 % of all snakebites [5].

Like other snake venoms, those of coral snakes are a complex mixture of enzymes, non-enzymatic proteins, peptides, and other less abundant molecules such as lipids, ions, and nucleosides [6]. Venoms from the Micrurus genus are mainly composed of phospholipases A2 (PLA2) and three-finger toxins (3FTx) [7,8]. Both protein families can have neurotoxic representatives, which act on the neuromuscular synapse and cause flaccid paralysis of muscles due to nerve impulse blockage [9]. Neurotoxic PLA2s, also known as β-neurotoxins (β-NTx), act at the presynaptic level by preventing the release of acetylcholine at the synapse and causing lysis of the presynaptic button, [10]. Conversely, alpha-neurotoxins (α-NTx) from the 3FTx family act at the postsynaptic level as neurotransmitter antagonists, preventing the opening of the ion channel and, thus, inhibiting nerve transmission. Both groups induce flaccid paralysis of skeletal muscles and may cause symptoms such as pain, palpebral ptosis, mild local edema, erythema, dysphagia, dyspnea, myalgia, fasciculations, and respiratory failure with minimal or no damage to other organs. These effects can ultimately lead to death [[11], [12], [13]].

Toxins with synergistic effects have been reported in snake venoms; however, such synergies are less documented in coral snake venoms [14]. This might be because many venom component separations are typically performed using RP-HPLC, which often disrupts non-covalent protein-protein interactions, potentially resulting in the loss of lethal activity. Despite the limited number of clinically relevant protein families, coral snake venoms have variable compositional complexities [8]. Recently, protein complexes with neurotoxic effects were identified in the venom of Micrurus specimens from southern Mexico (Chiapas), previously identified as M. browni, although currently recognized as an undescribed species [4]. From this point on, we will refer to them as M. sp. from Chiapas [4]. A complex comprising at least one enzymatically active PLA2 and one 3FTx caused flaccid paralysis and death. Still, when tested individually, each component exhibited no noticeable toxic effects [14]. The proportion of neurotoxic PLA2s within the PLA2 family is low in this and other Mexican Micrurus species. Similarly, the percentage of 3FTxs with type I and II β-NTx sequences and activities are also low, compared to the vast diversity of 3FTxs with still unknown toxicities. For instance, in Micrurus tener from Tamaulipas, Mexico, 34 % of the venom proteins are PLA2s, of which only 14 % are β-NTxs, while 46 % are 3FTxs, with only 4 % being β-NTxs [15]. A similar pattern is seen in Micrurus sp. from Chiapas, where 48 % of the venom consists of PLA2s, but only 5.9 % are β-NTxs, and 31 % of the venom is composed of 3FTxs, with only 5 % being α-NTxs [14].

All the 14 species of Micrurus recorded from Mexico are of medical importance [5]. However, the composition and activities of many of the venoms of this genus have yet to be discovered, and only scarce information on their natural history is available. Such is the case of the coral snake population from Tehuacán Valley in the Mexican state of Puebla, which for many years was known as Micrurus pachecogili [16], however based on molecular data it was recently synonymized with Micrurus ephippifer, a member of the M. browni group [4].

This study aimed to analyze the transcriptome of the venom gland and the venom proteome, and to carry out the biochemical and functional characterization of M. ephippifer venom from Tehuacán, Puebla. Further, the possible synergisms in toxins, and the neutralization of this venom by the Mexican antivenom Coralmyn® were evaluated.