Brazilian researchers have potentially found an unusual source of blood pressure medication: snake venom.
Supported by the São Paulo Research Foundation (FAPESP), the researchers conducted two studies, unearthing novel peptides with potential biotechnological applications from the venoms of the lancehead pit viper Cotiara (Bothrops cotiara) and the South American bushmaster (Lachesis muta).
Despite decades of research and numerous studies, snakes and spider venoms never cease to surprise scientists, with these studies highlighting the untapped wealth of information hidden within their venoms.
Principal investigator Alexandre Tashima, a professor at the Federal University of São Paulo’s Medical School, expressed his awe in a statement, saying, “Even with so much accumulated knowledge, fresh discoveries are possible, such as unpredictable fragments that are parts of known proteins.”
From venom to life-altering medicine
The first study focused on the lancehead pit viper Cotiara, revealing a novel peptide named Bc-7a. Although it is part of a protein causing bleeding in the snake’s prey, it is, in functional terms, closer to peptides responsible for drugs like captopril, which lowers blood pressure by inhibiting the activity of angiotensin-converting enzyme (ACE).
Although many ACE-inhibiting molecules already exist, these present adverse side effects in the form of dry cough, dizziness, and high blood potassium levels.
The study, published in the journal Biochimie, identified a total of 197 peptides, with 189 being reported for the first time. The research team found 73 peptides in the venom of the same species, in 2012. The leap in discoveries ever since is attributed to advanced technology which enabled faster and more sensitive equipment along with an increase in available peptide sequences from databases.
A peptide for blood pressure control
The second study centered around the South American bushmaster venom and identified 151 peptides, of which 126 were previously unknown. Of particular interest is the Lm-10a peptide, derived from a metalloproteinase (protease enzyme whose catalytic mechanism involves a metal).
This Lm-10a peptide not only inhibits ACE but also holds the potential for treating blood pressure issues. Researchers believe that both Lm-10a from L. muta and Bc-7a from B. cotiara result from fragmentation processes during venom maturation, suggesting a complex interplay of biological mechanisms in venom evolution.
“In this kind of analysis, the protein sequence obtained is just a snapshot,” Tashima explained. “Cleavage, enzymatic degradation and other processes generating novel peptides that aren’t necessarily detected occur all the time.”
While these discoveries are promising, further research is imperative to unlock the true potential of these peptides. Tashima emphasized the dynamic nature of toxin maturation, indicating that the evolving nature of venomous snakes' toxins could offer even more insights into the realm of peptides and their biological roles.
"Despite advances in sequencing technology, much remains to be discovered about the vast universe of peptides and their biological roles,” Tashima concluded. “We must take advantage of our good fortune in being able to study these species, many of which will be extinct before they’ve even been discovered."
Study Abstract
Snake venoms are primarily composed of proteins and peptides, which selectively interact with specific molecular targets, disrupting prey homeostasis. Identifying toxins and the mechanisms involved in envenoming can lead to the discovery of new drugs based on natural peptide scaffolds. In this study, we used mass spectrometry-based peptidomics to sequence 197 peptides in the venom of Bothrops cotiara, including a novel 7-residue peptide derived from a snake venom metalloproteinase. This peptide, named Bc-7a, features a pyroglutamic acid at the N-terminal and a PFR motif at the C-terminal, homologous to bradykinin. Using FRET (fluorescence resonance energy transfer) substrate assays, we demonstrated that Bc-7a strongly inhibits the two domains of angiotensin converting enzyme (Ki < 1 μM). Our findings contribute to the repertoire of biologically active peptides from snake venoms capable of inhibiting angiotensin-converting enzyme (ACE), beyond current known structural motifs and precursors. In summary, we report a novel snake venom peptide with ACE inhibitory activity, suggesting its potential contribution to the hypotensive effect observed in envenomation.