From Alzheimer’s to Zebrafish: Eclectic Science and Regulatory Stories 34
With the introduction of exenatide and ziconotide in 2005, the field of medicine now
includes drugs directly derived from lizards and snails. Exenatide is made from the saliva
of the Gila monster and is used in treating type 2 diabetes mellitus. It is the first in a new
class of drugs called incretin mimetics. Ziconotide is the synthetic equivalent of a poly-
basic peptide present in the venom of Conus magus, a marine snail. The drug is the first
selective N-type, voltage sensitive, calcium channel (VSCC) blocker and is used to treat
patients with refractory pain due to any underlying pathology including AIDS or cancer.
The history of these discoveries is as interesting as the drugs themselves. Other venom-
based products, now deemed “pharmazooticals,” are in development. This article briefly
examines precursors, venoms, snakes, cone snails, the Gila monster, ziconotide, exenatide
and the future development of drugs using new sources.
Earlier Developments
Neurologist and novelist S. Weir Mitchell may have been the first person to research
and publish the effects of poisonous snakes. Dr. Mitchell was one of the most prominent
physicians of the late 19th and early 20th centuries. In 1862, the Smithsonian Institute
published Mitchell’s 145-page monograph, entitled “Researches Upon the Venom of
the Rattlesnake.” His interest continued for almost 50 years with studies conducted on
rattlesnakes, cobras, water moccasins and copperheads. He discovered that rattlesnake
venom was an albuminous complex compound containing two separate poisons that he
called venom peptone and venom globulin. The latter, according to Dr. Mitchell, was more
virulent and destructive: it enfeebled the heart, attacked the respiratory system and finally
paralyzed the spinal ganglia. He had no explanation for the mechanism, only that some
mysterious alteration is present. (The existence of neurotransmitters was not confirmed
until the early 1900s.) Dr. Mitchell also was aware of the Gila monster, describing it as a
“good humored” and hideous reptile, difficult to induce to bite anyone. He did note that
once it takes hold, no bulldog could be more tenacious. The Gila monster’s saliva was said
to smell like magnolia buds and the venom was a deadly heart poison.1
Earlier Drugs
Exenatide and ziconotide are unique, but they are not the first drug products derived from
venom. There have been a number of antivenin preparations available to treat snakebite,
and equine-derived antivenin has been the mainstay of hospital treatment for venom-
ous snakebite for more than 35 years.2 Antivenin is an antibody preparation derived from
horses or sheep injected with non-lethal amounts of snake venom.3 Antivenin (Crotalidae)
Polyvalent has been the standard available treatment for rattlesnake, cottonmouth and
copperhead bites. Eastern US coral snakebites require Antivenin (Micrurus fulvius). A
sheep-derived antivenin, CroFab (Crotalidae Polyvalent Immune Fab), which is much less
allergenic, also has received approval from the US Food and Drug Administration (FDA)
for treating snakebites.4 Due to their manufacturing method and passive use, none of the
antivenin products can be considered therapeutic venoms.
Clotting enzymes from snake venoms have been used to treat thromboembolic dis-
eases, and other enzymes from the same sources are also important diagnostic reagents
in hemostasis. Reptilase is used to differentiate causes of prolonged thrombin time. It is
derived from the venom of Bothrops atrox. Captopril, the first of a series of ACE inhibitors,
is the first example of a drug derived from venom. Captopril was developed from struc-
tural relationship studies of teprotide, a peptide from Bothrops jararaca (a South American
pit viper) venom.5 This substance was found to inhibit the activity of angiotensin-convert-
ing enzyme, an enzyme that raises blood pressure.
Tirofiban (Aggrastat) and eptifibatide (Integrilin), drugs used to inhibit platelet
aggregation, are similar to the proteins in snake venom that cause bleeding. Tirofiban was
based on the venom of the African saw-scaled viper, while studies on the venom of the
With the introduction of exenatide and ziconotide in 2005, the field of medicine now
includes drugs directly derived from lizards and snails. Exenatide is made from the saliva
of the Gila monster and is used in treating type 2 diabetes mellitus. It is the first in a new
class of drugs called incretin mimetics. Ziconotide is the synthetic equivalent of a poly-
basic peptide present in the venom of Conus magus, a marine snail. The drug is the first
selective N-type, voltage sensitive, calcium channel (VSCC) blocker and is used to treat
patients with refractory pain due to any underlying pathology including AIDS or cancer.
The history of these discoveries is as interesting as the drugs themselves. Other venom-
based products, now deemed “pharmazooticals,” are in development. This article briefly
examines precursors, venoms, snakes, cone snails, the Gila monster, ziconotide, exenatide
and the future development of drugs using new sources.
Earlier Developments
Neurologist and novelist S. Weir Mitchell may have been the first person to research
and publish the effects of poisonous snakes. Dr. Mitchell was one of the most prominent
physicians of the late 19th and early 20th centuries. In 1862, the Smithsonian Institute
published Mitchell’s 145-page monograph, entitled “Researches Upon the Venom of
the Rattlesnake.” His interest continued for almost 50 years with studies conducted on
rattlesnakes, cobras, water moccasins and copperheads. He discovered that rattlesnake
venom was an albuminous complex compound containing two separate poisons that he
called venom peptone and venom globulin. The latter, according to Dr. Mitchell, was more
virulent and destructive: it enfeebled the heart, attacked the respiratory system and finally
paralyzed the spinal ganglia. He had no explanation for the mechanism, only that some
mysterious alteration is present. (The existence of neurotransmitters was not confirmed
until the early 1900s.) Dr. Mitchell also was aware of the Gila monster, describing it as a
“good humored” and hideous reptile, difficult to induce to bite anyone. He did note that
once it takes hold, no bulldog could be more tenacious. The Gila monster’s saliva was said
to smell like magnolia buds and the venom was a deadly heart poison.1
Earlier Drugs
Exenatide and ziconotide are unique, but they are not the first drug products derived from
venom. There have been a number of antivenin preparations available to treat snakebite,
and equine-derived antivenin has been the mainstay of hospital treatment for venom-
ous snakebite for more than 35 years.2 Antivenin is an antibody preparation derived from
horses or sheep injected with non-lethal amounts of snake venom.3 Antivenin (Crotalidae)
Polyvalent has been the standard available treatment for rattlesnake, cottonmouth and
copperhead bites. Eastern US coral snakebites require Antivenin (Micrurus fulvius). A
sheep-derived antivenin, CroFab (Crotalidae Polyvalent Immune Fab), which is much less
allergenic, also has received approval from the US Food and Drug Administration (FDA)
for treating snakebites.4 Due to their manufacturing method and passive use, none of the
antivenin products can be considered therapeutic venoms.
Clotting enzymes from snake venoms have been used to treat thromboembolic dis-
eases, and other enzymes from the same sources are also important diagnostic reagents
in hemostasis. Reptilase is used to differentiate causes of prolonged thrombin time. It is
derived from the venom of Bothrops atrox. Captopril, the first of a series of ACE inhibitors,
is the first example of a drug derived from venom. Captopril was developed from struc-
tural relationship studies of teprotide, a peptide from Bothrops jararaca (a South American
pit viper) venom.5 This substance was found to inhibit the activity of angiotensin-convert-
ing enzyme, an enzyme that raises blood pressure.
Tirofiban (Aggrastat) and eptifibatide (Integrilin), drugs used to inhibit platelet
aggregation, are similar to the proteins in snake venom that cause bleeding. Tirofiban was
based on the venom of the African saw-scaled viper, while studies on the venom of the