By Steve Trim, founder and chief scientific officer, Venomtech
There are in excess of 100,000 extant venomous animal species globally, each producing a chemical cocktail of up to 1,000 different components. This includes a diverse array of different peptides, proteins, and non-peptide small molecules. Many of these molecules have evolved to be highly specific, and they often act on targets of pharmacological interest, offering significant potential for the development of new therapeutics.
There is a general lack of awareness of the potential of venom-derived compounds for drug development in the research community. One of the main reasons for this is that many view these compounds as simple peptides that will be easily digested, severely limiting their potential for therapeutic use. This is despite the fact that several of these non-antibody biologics are already launched drugs and successfully being used as the basis for drug development across different indications, as outlined below. The other common misconception is that venom-derived compounds are only suitable for the development of cytotoxins, hemotoxins, or neurotoxins and not as a viable source to produce a wider variety of drugs. This stems from a limited understanding of how natural selection has honed the function of these compounds on their targets. There is a lot more for us to discover in this area and some of the answers are likely to come from drug discovery.
Advantages And Current Therapeutic Uses Of Venom-Derived Compounds
Venom-derived compounds often have improved selectivity and efficacy compared to many small molecules, particularly for challenging targets such as ion channels. Most venoms have also been refined through millions of years of evolution to be very stable, even under a variety of abiotic conditions, making them well suited to drug development for many therapeutic indications. A number of these drugs are already licensed and are currently being used in healthcare and clinical settings.
One example of a venom-derived drug launched onto the market is the angiotensin-converting enzyme (ACE) inhibitor Capoten and later versions, such as ramipril (Tritace). Capoten was the very first therapeutic derived from venom to be licensed for use1-3 and also the first antihypertensive.4 This small molecule mimics the ACE inhibition discovered from the Brazilian pit viper (Bothrops jararaca),5 a venom that is rich in bradykinin potentiating peptides, which are now well understood as regulators of blood circulation homeostasis. In nature, snakes deliver these peptides through their venom to block production of angiotensin II and inhibit somatic ACE, thus subsequently lowering prey blood pressure and causing them to lose consciousness. These properties were used in the identification of captopril, the very potent active compound of Capoten. The effectiveness of this drug is attributed to the synthetic molecule’s proline residue in the substrate-binding pocket of ACE and, secondly, a thiol moiety that matches with the zinc at the enzyme’s active site.5
Another example is the use of glucagon-like peptides (GLPs), which are normally transiently expressed before being rapidly metabolized. However, the Gila monster – a venomous lizard – has developed a highly stable version of GLP-1, which can survive in its venom glands for months at a time. Exenatide, a medication derived from Gila monster venom that is used for the treatment of type 2 diabetes,5 is an effective GLP-1 analog6 due to its half-life of hours within human plasma. It therefore has greater bioavailability and stability when circulating in the human body compared with the human peptide.
The last example discussed in this article, although there are many more,5 is ziconotide. This is an atypical analgesic drug developed from a ω-conotoxin peptide7 found in the venom of the Magician’s Cone Snail (Conus magus).5 Ecologically, this peptide evolved to paralyze fish prey rapidly and efficiently by blocking the CaV2.2 subtype of voltage-gated calcium-ion channels.5,8 However, its synthetic therapeutic counterpart, ziconotide, uses this modulation of CaV2.2 ion channels to provide effective relief in patients with severe or chronic pain.5 It has been said to be orders of magnitude more potent than morphine and does not lead to addiction or tolerance after prolonged administration,9 so it is a treatment that exhibits many significant benefits to patients.
The Secret To Their Success: Reduced Toxicity And Improved Selectivity Profile
Most venom-derived compounds are not toxic at low doses. Coupled with the high specificity many of these peptides offer, this enables effective treatment regimens to be developed while minimizing off-target effects. An example of this excellent specificity is the recent discovery of binding inhibitors for programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1). Two separate three-finger toxins – a superfamily of small toxic proteins originating in elapid snakes – have been shown to disrupt PD-1/PD-L1 binding, where small molecules have previously failed. These proteins are now being optimized through SAR (structure-activity relationships) to identify the active site and potential therapeutic applications.10
Another example of this is in voltage-gated sodium (Nav) channel research. Targeting these channels can provide insights into treatment of pain, epilepsy, and paralysis, but small molecule drugs struggle to achieve sufficient subtype selectivity to minimize off-target effects. However, a recent collaboration has identified several new venom-derived peptides that exhibit high potency and selectivity for the Nav1.7 subtype, a key target for pain management.11 This body of work adds to the large number of arachnid peptides known to modulate sodium channels and demonstrates that there are many more to be found. This diversity makes them attractive tools for the development of innovative therapeutics for Nav channel modulation, while minimizing off-target effects due to the high-power SAR potential.11
Lastly, free fatty acids (FFAs) participate in physiological processes through interaction with G-protein coupled receptor 120 (GPR120). Agonism of GPR120 has been shown to help prevent metabolic disorders – such as obesity and diabetes – making it a therapeutic potential target. It was discovered that peptides in venom fractions from Naja siamensis (Indochinese spitting cobra) acted as a novel class of agonists of GPCR120, allowing chemists to more away from the natural fatty acid ligands. It is yet to be shown if these peptides offer improved regulation of lipid and glucose metabolism in adipose, liver, and muscle tissues compared to natural FFAs, but novel compound classes such as this open up a new range of possibilities and avenues for exploration.12
The Benefits Of Screening Venom-Derived Compounds In Drug Discovery
Traditional drug discovery relies on a wide range of screening approaches to identify candidate molecules that interact with the target of interest. However, using venoms in these screens has been challenging due to the complex nature of these mixtures. This has been simplified through a proprietary Targeted-Venom Discovery Array (T-VDA) approach, enabling identification of compounds of interest, hit validation, and proof of concept or mechanistic studies, guiding downstream modification to improve drug stability or bioavailability.
Venom libraries offer an opportunity for rapid identification of novel hits and leads through simple, systematic screening of very stable compounds5 against different target and assay types. Screening libraries are selected using a knowledge of venom pharmacology and evolutionary biology. This ensures that libraries only include those venoms with the highest chance of elucidating hits against the chosen target.13
The Future Of Venoms In Drug Discovery
There is still a stigma around the use of venoms in drug discovery, as they are not generally known as “drug-like” molecules. As a result, venom-derived compounds are often considered a last resort for the development of novel therapeutics once other approaches to target a receptor or pathway of interest have already failed. However, recent successes outlined here indicate that this perception is changing.10-12 As venom-derived compounds become more widely accepted as a viable choice at the outset of a drug discovery project – which can prevent failures against difficult targets – venom suppliers need to provide more user-friendly, workflow-oriented solutions capable of meeting the needs of this fast-paced environment. This will help the process of venom-based drug development – from initial identification of a hit to fully registered and marketed drug – faster, simpler, and less costly for project managers. Venoms have now established their place in the future of drug discovery, and the message is clear: the applications of these compounds go far beyond last-ditch solutions to rescue stalled projects and into first-line screens.
- El-Aziz, T.M.A., Soares, A.G., and Stockland, J.D. Snake venoms in drug discovery: valuable therapeutic tools for life saving. Toxins. 2019;11(10):564.
- Camargo, A.C.M., Ianzer, D., Guerreiro, J.R., and Serrano, S.M.T. Bradykinin-potentiating peptides: beyond captopril. Toxicon. 2012;59(4):516-523.
- Dinicolantonio, J.J., Lavie, C.J., and O’Keefe, J.H. Not all angiotensin-converting enzyme inhibitors are equal: focus on ramipril and perindopril. Postgrad Med. 2013;125(4):154-168.
- Scarborough, R.M., Naughton, M.A., Teng, W., Rose, J.W., Phillips, D.R., Nannizzi, L., and Arfsten, A. Design of potent and specific integrin antagonists. Peptide antagonists with high specificity for glycoprotein IIb-IIIa. J Biol Chem. 1993;268(2):1066-1073.
- Trim, C.M., Byrne, L.J., and Trim, S.A. Chapter one – Utilisation of compounds from venoms in drug discovery. Prog Med Chem. 2021;60:1-44.
- Furman, B.L. The development of Byetta (exenatide) from the venom of the Glia monster as an anti-diabetic agent. Toxicon. 2012;59(4):464-471.
- Miljanich, G. Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr Med Chem. 2004;11(23):3029-3040.
- Sousa, S.R., AcAruthur, J.R., Brust, A., Bhola, R.F., Rosengren, K.J., Ragnarsson, L., Dutertre, S., Alewood, P.F., Christie, M.J., Adams, D.J., Vetter, I., and Lewis, R.J. Novel analgesic ω-conotoxins from the vermivorous cone snail Conus moncuri provide new insights into the evolution of conopeptides. Sci Reports. 2018;8(13397):1-15.
- McGivern, J.G. Ziconotide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatr Dis Treat. 2007;3(1):69-85.
- Trim, S.A., McCullough, D., Baker, S., and Grant, P. Novel biologics for disrupting programmed cell death receptor PD-1 binding to PD-L1. Poster presented at European Laboratory Research Interest Group Drug Discovery 2021. Poster number 49. https://venomtech.co.uk/wp-content/uploads/2022/01/S-Trim-ELRIGDD-2021-PD-1-poster-49-final.pdf
- Duncan, E.M., McCullough, D., Grace, S., Baker, S., Kammonen, J., Grant, P., Trim, S.A., and Lazari, V. Identifying novel and selective sodium channel modulators from Theraphosidae venoms. Poster Presented at Society for Neuroscience: Neuroscience 2021. Poster number P093.0. https://venomtech.co.uk/wp-content/uploads/2022/01/Venomtech-CRL-SfN-Poster-005.pdf
- McCullough, D., Trim, S.A., Baker, S., and Grant, P. Novel GPCR Ligands: GPR120 Case Study. Poster presented at European Laboratory Research Interest Group Drug Discovery 2021. Poster number 46. https://venomtech.co.uk/wp-content/uploads/2022/01/Venomtech-ELRIGDD-2021-GPCR-poster-final.pdf
- Williamson, H.K., Bennett, N., and Walsh, J. Activating Challenging GPCR Targets with Venom Peptides. Poster presented at European Laboratory Research Interest Group Drug Discovery 2017. https://venomtech.co.uk/wp-content/uploads/2021/12/ELRIG-2017-Venoms-Poster_GD.pdf
About The Author:
Steve Trim is the founder and chief scientific officer at Venomtech Ltd, a U.K. biotech company set up in 2010 to provide assay ready venom fraction libraries for drug discovery. He started his drug discovery career with 10 years as a molecular biologist, biochemist, and safety delegate at Pfizer global research and development. He has won awards for animal welfare, holds a patent for safe methods of feeding venomous snakes, and received the 2013 ELRIG technology prize for launching the first 384-well acoustically dispensable venom library. Trim received chartered biologist status from the Royal Society of Biology in 2016, is chair of the Veterinary Invertebrate Society, and is an ELRIG committee member.