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Toxins affecting the cardiovascular system
The first venom-based drug captopril discovered in 1975
also formed the first oral angiotensin-converting enzyme
(ACE) inhibitor. This success storystarted with the observation of the toxic effect of venom from a Brazilian
viper (Bothrops jararaca) that caused a sudden, massive
drop in blood pressure. This piqued the interest of Nobel Prizewinner Sir John Vane, who found that the viper venom was a potent inhibitor of ACE. Vane took this
discovery to the pharmaceutical company Squibb where
two scientists, David Cushman and MiguelOndetti, created captopril, the first oral ACE inhibitor [18]. With the
success of captopril, snake venoms have been explored
for potential applications pertaining to the cardiovascular
system. Thebinding of the anti-hypertensive drug captopril to its substrate ACE is shown in Figure 1c.
A toxin isolated from Indian cobra venom in the late
1940s was named cardiotoxin because it caused cardiacarrest when injected into experimental animals. Cardiotoxins, also known as cytotoxins are found exclusively in
the venom of cobras and ringhals [19, 20], and are direct
lytic factors andmembrane-active polypeptides. They
are single-chain, highly hydrophobic, basic, short polypeptides closely related to the α-neurotoxin that binds to
nAChR, but cardiotoxins do not show any significantaffinity for the receptors [21]. The main targets of cardiotoxins are on excitable cells. They cause depolarization
and contracture of cardiac, skeletal and smooth muscles,
and depolarization andloss of excitability of nerves.
Figure 1. (a) Structure of the α-cobratoxin-AChBP complex (1YI5) [from ref. 88]. (b) Nuclear magnetic resonance structure of an AChRpeptide (Torpedo californica, alphasubunit residues 182–202) in complex with α-bungarotoxin (1L4W) [from ref. 89]. (c) Complex of the
anti-hypertensive drug captopril and the human testicular angiotensin I-converting enzyme (1UZF)...