Animal
venoms are rich in hundreds of toxins with extraordinary
biological activities. Their exploitation is difficult due to their
complexity and the small quantities of venom available from most venomous
species. We developed a Venomics approach combining transcriptomic
and proteomic characterization of 191 species and identified 20,206
venom toxin sequences. Two complementary production strategies based
on solid-phase synthesis and recombinant expression in Escherichia coli generated a physical bank of 3597
toxins. Screened on hMC4R, this bank gave an incredible hit rate of
8%. Here, we focus on two novel toxins: N-TRTX-Preg1a, exhibiting
an inhibitory cystine knot (ICK) motif, and N-BUTX-Ptr1a, a short
scorpion-CSαβ structure. Neither N-TRTX-Preg1a nor N-BUTX-Ptr1a
affects ion channels, the known targets of their toxin scaffolds,
but binds to four melanocortin receptors with low micromolar affinities
and activates the hMC1R/Gs pathway. Phylogenetically, these two toxins
form new groups within their respective families and represent novel
hMC1R agonists, structurally unrelated to the natural agonists.
The melanocortin 4 receptor (MC4R) plays a role in energy
homeostasis
and represents a target for treating energy balance disorders. For
decades, synthetic ligands have been derived from MC4R endogenous
agonists and antagonists, such as setmelanotide used to treat rare
forms of genetic obesity. Recently, animal venoms have demonstrated
their capacity to provide melanocortin ligands with toxins from a
scorpion and a spider. Here, we described a cone snail toxin, N-CTX-Ltg1a,
with a nanomolar affinity for hMC4R but unrelated to any known toxins
or melanocortin ligands. We then derived from the conotoxin the linear
peptide HT1-0, a competitive antagonist of G
s, G
15, and β-arrestin2 pathways
with a low nanomolar affinity for hMC4R. Similar to endogenous ligands,
HT1-0 needs hydrophobic and basic residues to bind hMC4R. Altogether,
it represents the first venom-derived peptide of high affinity on
MC4R and paves the way for the development of new MC4R antagonists.
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