Snakes alive: Venom may play a role in the fight against COVID-19

Things can change quickly in medical science, especially during a pandemic.

Rewind to 2018, and Monash University pharmacologist Dr Sanjaya Kuruppu wins a prestigious grant from the United States to research a peptide from a deadly snake that may prevent Alzheimer’s disease.

The team he co-leads gets to work – with new funding from the US government’s National Institutes of Health (NIH) – on investigating a molecule from the Bothrops asper, a pit viper from South and Central America.

It is an aggressive snake that accounts for the most snake-bite deaths in the region. But its venom looks like it can counter the toxic protein amyloid beta, which is a cause of Alzheimer’s disease; a molecule in the venom perks up two enzymes that clear amyloid beta.

On the team are Dr Kurrupu’s mentor, Professor Ian Smith, Monash University’s Vice-Provost (Research and Research Infrastructure); Professor Helena Parkington from Monash’s Biomedicine Discovery Institute (BDI); and Dr Niwanthi Rajapakse, a senior lecturer at the University of Queensland. Dr Kuruppu works for the Monash Venom Research Laboratory (within BDI) from the University of Queensland.

Researchers found the peptide they were already looking at for Alzheimer’s disease may help in the fight, or future fights, against COVID-19.

In the two years or so since, they tweak their synthesised peptide to try and make it work better on the Alzheimer’s protein in the brain. They begin finding ways to make it cross the blood-brain barrier, making it potentially more effective. Because peptides break down easily in the bloodstream, they work on improving its stability.

A turning point in the lab as COVID-19 appears

Then, on New Year’s Eve last year, everything in medical science changed. Health authorities report a cluster of apparent pneumonia cases in Wuhan, China.

It was, in fact, a new strain of an acute respiratory coronavirus – COVID-19. Two weeks later the first case was found outside China, in Thailand. Now, in May, more than 200,000 are dead, making it the worst pandemic since the Great Plague of the 1600s.

In the team’s lab, too, everything changed. The researchers found the peptide they were already looking at for Alzheimer’s disease may help in the fight, or future fights, against COVID-19.

“It binds to an enzyme which plays an important role in the cardiovascular system,” Dr Kuruppu says. The enzyme in question is called angiotensin-converting enzyme 2.

“Activating this enzyme also causes improvements in vascular function – it makes the blood vessels relax. This enzyme is also the receptor for COVID-19. Very early studies show it can stop the binding of proteins [the “spikes” in commonly seen images of the virus] to the cells. We found this very recently, and this is very preliminary, but it shows a lot of promise.”

Snake venom – the great untapped resource

Snake venom has long been of peculiar interest to pharmacologists. They love the stuff, because, despite differing components between species, it’s full of weird and wonderful peptides, enzymes, neurotoxins and proteins, making it a complex and interesting “soup” that can kill, and also cure. Lizard and cone snail venoms are also useful.

In 1980, the first modern hypertension drug, sold as Captopril, came on the market. It was made from snake venom, from the same family of South American pit vipers now being re-examined during the COVID-19 pandemic.

The head of the Monash Venom Research Group, Professor Wayne Hodgson, says venom is still an untapped resource. “We still have a poor understanding of the effects of many venoms, including snake venoms, fish venoms, and spider venoms,” he says. “Australia and the Asian region are home to some of the world's most venomous animals, so it’s a great opportunity to study these venoms. Not only can we learn about the likely clinical effects of these venoms and identify potential treatment strategies, there are a number of therapeutic agents that have been developed based on venom components.”

Another of his lab members, Ms Rahini Ragavan Kakumanu, a PhD candidate and teaching associate, has two recent papers published, exploring snake venom and its links to both cardiovascular collapse and extreme blood pressure changes in the person “envenomed”.

Ms Kakumanu also studies venom from the vampire bat, a strange nocturnal mammal that feeds only on blood, mainly from livestock. It’s often the creepiest creatures that have the most to offer science.

Professor Hodgson says the link between venoms and cardiovascular collapse was a murky area. “It was unclear whether these snake venoms were capable of causing collapse, or whether they produced different effects on the cardiovascular system which were shorter in duration – that is, transient – and less likely to cause fatalities.

“Previous research has focused heavily on the neurotoxic effects of snake venoms, or the effects of snake venoms on blood coagulation,” he says. “However, there are a number of snakes which cause significant effects on the cardiovascular system, including rapid cardiovascular collapse, which can be fatal.”

"Australia and the Asian region are home to some of the world's most venomous animals, so it’s a great opportunity to study these venoms."

Ms Kakumanu looked at seven deadly snakes – the Australian eastern brown, the Sri Lankan Russell’s viper, the Javanese Russell’s viper, the Gaboon viper (Africa), the Uracoan rattlesnake (Venezuela), the carpet viper (Asia and the Middle East), and the puff adder (Morocco and Africa).

“I wanted to see if there is any link between the different types of venoms and cardiovascular effects, or if there’s a particular toxin they all have in common which causes either hypotension [low blood pressure] or hypertension [high blood pressure],” she says.

“I have also investigated the mechanism of cardiovascular collapse, which is a very common symptom from the brown snake envenomation in Australia. We weren’t quite sure what was causing collapse. Now we have shown there are two distinct mechanisms – one that causes low blood pressure that you can revive from, and sudden cardiovascular collapse that usually leads to death.”

The paper distinguishes between the two effects on the human body for the first time.

The Russell’s viper species interest her greatly. They’re named after the pioneering Scottish herpetologist Patrick Russell, who, in the late 1700s, travelled through India looking for dangerous snakes, and documenting them.

“The Russell’s viper is found throughout Asia; however, interestingly, the venom is slightly different in each region,” she says. “We thought the snake caused cardiovascular collapse, but through my research we now know it causes hypotension that you can recover from. The Australian brown snake and the carpet viper from Nigeria, despite being two different species of snake, cause cardiovascular collapse, but through a very similar mechanism.”

That “mechanism”, though, is unclear. “We think once you are bitten, the venom is causing your body to release factors in the body that causes blood pressure to drop. It can do this suddenly, or slowly. Russell’s viper venom contains toxins that cause blood pressure to decrease via potassium channels found in our blood vessels, while the Australian brown snake and the carpet viper do not.”

Snakes. They can kill you, quickly and painfully. Or they can cure, maybe better than we already knew.

 Sanjaya Kuruppu was a Research Fellow in Monash's Department of Biochemistry and Molecular Biology at the time of writing this article.  He has since moved on from Monash.