Nowadays, many people tend to think of wildlife as the source of certain human diseases, but if we look back at the history of medicine, we will find that humans have been using animals for their own health.
40,000 years ago, Neanderthals used poplar bark as a painkiller, and plants entered the medicine cabinets of ancient humans; on the other hand, the medicinal history of animals is also quite long.
From traditional medicine to modern chemistry
Traditional Chinese medicine extracts ingredients that contribute to human health from 36 species of wild animals, including rhinos, black bears, tigers and seahorses, many of which are now endangered. Traditional Indian medicine recommends the use of snake venom for arthritis. South America, Asia and Africa have a long tradition of treating diseases ranging from cancerous tumors to toothaches and asthma using tarantula bites or their poisonous fangs (after grinding).
Traditional medicine in many places recommends the use of treatments of animal origin, and traditional Indian medicine, which has a history of thousands of years, is just one of them
The vast majority of these traditional therapies are not supported by any scientific evidence, and the human quest for animal organs has led to the extinction of some species, such as the black rhino in West Africa and the white rhino in the north.
If we want to scientifically and rigorously apply wild animals to medicine, we must first study their chemical composition at the molecular level. Thanks to modern technology, it is possible to analyze an animal's composition without damaging it – just getting the DNA sequence.
Humans have been trying to isolate specific compounds from plants and convert them into drugs for more than a hundred years; unlike plants, specific molecules in animals that have potential medical value are extremely difficult to locate and extract.
But the conundrum is gradually being solved, and in the near future, we may have the confidence to say that while many diseases come from animals, some of the most exciting drugs will also be provided by animals.
Christine Beeton, an immunologist at Baylor College of Medicine in the United States, said: "We have studied plants for a long time, but our understanding of animals is still superficial. Beaton has long been working on how venom-derived peptides can be used to treat autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and dystrophy.
Researchers are extracting venom from rattlesnakes in São Paulo, Brazil
Peptides in venom, the new joy of modern medicine
The peptide chain is composed of several peptide bonds formed by the dehydration and condensation of several amino acids, and multiple peptide chains are multi-stage folded to form protein molecules. In a sense, we can think of peptides as "microproteins." But because the size of the peptide is 10 to 40 times that of small molecule drugs such as aspirin, its targetability is much higher, and the possibility of side effects is much smaller.
Today, with the help of tools such as genomics, proteomics, and transcriptomics, scientists have revolutionized the way in which molecules of medicinal potential are found in animals.
"Now we can screen for hundreds of compounds in a month," Beaton said. This wasn't possible until 15 years ago – you had to look at them one by one, and it could take up to 10 years. ”
Instead of having to laboriously squeeze the venom of snakes and scorpions and analyze them, researchers can simply dig up databases to find peptides with specific properties.
Many drugs of animal origin are now on the shelves:
Enexatide taken from gila's tarpon saliva can be used to treat type 2 diabetes;
Ziconitide, extracted from snail venom, is a good handle for chronic pain;
Eptifibatide, synthesized from the venom of the pygmy rattlesnake, can prevent heart attacks;
Batroxobin, extracted from the body of the South American spearhead viper, can be used for several different blood treatments;
Captopril, the first animal-derived drug, was approved by the FDA in 1981 as a blood pressure lowering drug.
Pygmy rattlesnake
Almost all of these animal-derived drugs originate from venom, one of the most complex chemical mixtures on earth. Many people may think that venom is a rare poison that only a few species have, but in fact 220,000 animal species (15% of all animal species) are known to be able to make them.
These poisons are extremely complex and delicate, and many of them have evolved over hundreds of millions of years, with excellent potency, stability, reaction speed, and, most critically, the ability to target specific molecular targets with precision.
Brain Guard
One of the most promising directions in the field of venom-derived drugs is the prevention of permanent brain damage caused by stroke.
Stroke is the second leading cause of death worldwide, killing 6 million people and permanently disabling 5 million people each year, and at this stage we cannot find any effective way to treat or prevent brain damage caused by stroke.
The only targeted drug currently approved by the FDA is tissue plasminogen activator (tPA), which can be used to break down blood clots in cerebral arteries, but it cannot prevent neuronal damage caused by hypoxia.
Glenn King, a biochemist at the University of Queensland in Australia, has long been working on neurological disorders. According to Kim, the root cause of neurological diseases is that nerve cell ion channels produce defects, ion channels run through cell membranes, control charged ions (such as sodium ions) in and out of cells and then produce nerve impulses, ion channel defects may be caused by abnormal channel structure or number of channels, and the main target of venom happens to be ion channels.
Being bitten by a funnel-shaped spider is enough to kill a person, but an ingredient in its venom is effective in helping strokers prevent brain damage
Kim extracted venom samples from more than 700 species of invertebrates, including scorpions, spiders, hunting midges and centipedes. These peptides taken from insects have a longer evolutionary history — perhaps 400 million years or more — than vertebrate toxins — and naturally have a stronger ability to target with precision.
In the process of tinkering with the insect venom reservoir, Kim found only one substance that seemed promising to cure stroke: Hi1a.
Hi1a is an ingredient in the venom of the Australian funnel spider (Hadronyche infensa), composed of 3,000 molecules, what Professor King calls "the world's most complex chemical weapons arsenal".
In a 2017 paper published in the Proceedings of the National Academy of Sciences (PNAS), King described the "neuroprotective" properties of Hi1a on stroke rats:
If Hi1a is given within 8 hours after stroke, those "serious damage" can be prevented; if it is administered within 4 hours, even if the dose is extremely small, it can prevent 90% of the damage.
On the other hand, although Hi1a is a toxin, its side effects are minimal, in Kim's words -
"'Toxins' are not necessarily poisonous to us, there are more than 100,000 species of spiders, but only a few are dangerous to humans." For example, Ziconitide, an analgesic derived from the venom of chicken heart snail, is lethal to fish, but when used in humans, it is a very common painkiller.
Chicken heart snails are devouring fish
Ion channels also seem to be a breakthrough in tackling another common neurological disease, epilepsy.
Severe infantile myoclonic epilepsy (Dravet syndrome, DS) is a developmental and epileptic encephalopathy that presents with symptoms in infancy, with a sudden death rate 30 times higher than other types of epilepsy. After studying Hm1a, a polypeptide taken from spider venom, Kim found that it was expected to become the terminator of DS.
Treatment of Dravet syndrome is extremely difficult, and the use of common prescription drugs such as Carbamezapine actually tends to make the condition worse. King published a paper in 2018 reporting the miraculous utility of Hm1a: A group of mice that had been genetically edited to obtain the same genetic defects as DS patients recovered normal neurological function and had a significant reduction in mortality after receiving Hm1a.
Anti-cancer weapon
At present, a tumor marker agent called Tozuleristide (BLZ-100) in the United States is in clinical trials and is expected to be approved by the FDA within two years.
Tozuleristide is derived from scorpion venom and is called "tumour paint" because it can attach to the surface of brain tumor cells and "color" tiny tumors that are difficult to detect even by MRI scans.
The story of the drug began in 2004 when Jim Olson, an oncologist at the Hutchinson Cancer Research Center, witnessed doctors failing to identify a thumb-sized piece of tumor tissue during a brain tumor resection operation that left the operation unsuccessful.
Since then, Olson has been determined not to let something like this happen again. He began leading the team in finding a molecule that would make tumor tissue visible to help surgeons see cancer with the naked eye.
After searching the DNA database for six weeks, Olson et al. identified a potential candidate— Chlorotoxin.
Chlorotoxin comes from the venom of the Israeli golden scorpion (Leiurus quinquestriatus), nicknamed "Death Stalker." In 1998, researchers discovered that chlorotoxin can attach to ion channels on the surface of brain tumor cells. In 2007, an article published in the journal Cancer Research suggested that chlorotoxin selectively binds to brain tumor cells rather than healthy cells.
In light of all of the above, scientists at hutchinson Cancer Research Center chose to combine chlorinated toxin with the fluorescent indicator Cy5.5 to create a tumor manifestation artifact, the aforementioned Tozuleristide.
Israeli Golden Scorpion
Tozuleristide helped the researchers see tumors that were only 200 cell sizes — nearly 500 times more sensitive than MRI scans. Other teams are investigating how to use Tozuleristide to label other forms of cancer, such as breast cancer and spinal tumors.
On the other hand, scientists are exploring animal-derived compounds that can kill cancer, not just label them.
Maria Ikonomopoulou, a researcher at the QIMR Berghofer Institute of Medicine in Australia, used a database to find that peptides from the venom of the Brazilian tarantula (Acanthoscurria gomesiana subspecies) kill skin cancer cells, and the venom of the Australian funnel spider can also kill cancer cells (while ensuring that it does not kill healthy skin cells).
In a 2018 article in Scientific Reports, Ikonomoplu described how he used "toxins" to treat melanoma.
The animals that provide medicinal venom are mainly snakes because they produce massive amounts of venom – but now we have a huge database that can retrieve the venom of animals that are not as strong as snakes.
A spider may produce only 10 ml of venom per day, a scorpion produces 2 ml per day, and a pseudo-scorpion can only produce less than 5 nanoliters of venom per day. But with the new database, researchers can synthesize enough specific chemical molecules on their own, based on large amounts of data.
Pain relief specialist
According to the U.S. Centers for Disease Control and Prevention, peptides from animals also show great potential in the treatment of chronic pain.
Chronic pain comes from a wide range of sources, from cancer to diabetic neuropathy to simple physical injuries, which can lead to pain experiences.
Venoms, which have evolved over millions of years, target the nervous system precisely, quickly, and powerfully, which is the chemical basis for their ability to demobilize prey or enemies. In fact, as long as humans understand and skillfully use them, they can be expected to achieve the use of poison to relieve pain. In the words of pain research specialist Irina Vetter:
Nature has done all the difficult chemistry for us, we just need to try to understand it better. Peptides derived from venom may have surprising, unusual, and extremely useful properties, such as Ziconitide from snail venom, which does not cause withdrawal symptoms compared to opioid painkillers.
In addition, Venom is also expected to provide new avenues for the treatment of autoimmune diseases. Animal-derived peptides now have shown extraordinary potential in the treatment of 80 autoimmune diseases, including multiple sclerosis, lupus and diabetes.
Now, scientists are delving into the possibility of using animal peptides to fight the coronavirus. Zachary Crook, the chief protein scientist at Olson's lab, is looking in the database for peptides that bind to spike proteins on the surface of SARS-CoV-2 to block the process of ACE-2 receptors on human cells to which the virus attaches.
Source:
The latest technology allows us to look for potential medicines in the natural world without collecting or harming a single animal – all you need is their DNA.
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