Harnessing the natural power of venoms
The pharmaceutical industry is facing some of its toughest ever challenges. For example, in terms of drug targets, many of the low hanging fruit have been picked long ago, and the ever cost of drug discovery and development has reached astronomical figures. We will need new approaches / ways of thinking in order to find new therapeutics that overcome these challenges. The potential of venoms as drug discovery tools or indeed sources of therapeutic agents has been known for many years! However, screening crude venoms to identify bioactive components is made extremely difficult by a large number of potentially conflicting activities (e.g. cytotoxic masking pharmacologic) and de-convolution challenges. In the past, these challenges have hampered many of the efforts to use venoms as drug discovery tools. Our goal at Venomtech Ltd is to enable venom-based drug discovery by providing targeted, high-quality venom preparations in a ready-to-use format. Our expertise unlocks the utility of thousands of novel molecules by providing peptide libraries grouped by molecular target, or disease area, in a plate based format, ready-to-use in both bench top and HTS platforms.
Venoms: what are they and why should they be effective?
Animal venoms are a complex mixture of peptides, small molecules and proteins that bind, activate, inhibit or otherwise modulate molecular targets such as ion channels, GPCRs and kinases. Often they have exquisite potency and selectivity, possibly because they have been developed through millions of years of evolution, rather than a few hundred years of drug discovery. It is true that animal venoms have not evolved to cure our diseases, but it’s also true that the targets they have been designed to hit in their prey have also evolved, for example, the closest orthologue to the mammalian voltage gated sodium channel NaV1.7 (Gene scn9a) in Drosophila is called paralytic (para). In humans, we find non-functional mutations in SCN9a that confer a congenital insensitivity to pain, whereas, similar orthologue mutations in flies are often lethal, or produce significant locomotor defects (FlyBase link). Thus, it is clear to see, how a venom that evolved to kill insects by blocking this channel has an innate potential as therapeutic agent in treating pain. In contrast, we also see venom activities that defy our current evolutionary understanding e.g. snake venom disintegrins that are anti-metastatic but have not evolved to cure cancer, but have evolved for some other purpose, yet to be elucidated.
Venoms in the clinic
To date there are 15 venom-derived drugs marketed (several with peak sales >$0.5B) and >14 new compounds in clinical trials. Such successes include the first ever anti-hypertensive Captopril, and it’s successors. Snake venom from the Fer-De-Lance inspired researchers to investigate how this snake caused extreme hypotension in its victims. Using the snake venom peptide as a tool lead to the connection of angiotensin and blood pressure, thus the ACE inhibitor series of compounds were launched, saving millions of lives. Other successes have been in clot busters such as Integrilin from rattlesnakes and a glucagon like peptide from Ghila monster venom.
Venomtech Targeted-Venom Discovery Arrays (T-VDAs)
For those new to Venomtech Ltd. we offer GPCR, kinase, anti-microbial and ion channel T-VDAs that contain 1D or 2D HPLC fractions from 12 different species, in Echo qualified 384 and 1,536 plates. These arrays are produced using our library of 20,000 potential fractions with full control from source species to standardised plates. Having full control of the supply chain, means that every venom fraction can be tracked back to the pool of animals that produced it, and thereby introduce a high level of quality control, whatever scale of production. We’ve won awards for our husbandry and have patents on our safe working practices, for total piece of mind. When combined with our Hit-2-Lead follow up service, our T-VDAs provide a unique opportunity to identify novel screening tools and to discover novel therapeutics.
Our own research efforts, using our own libraries, have already shown novel hits on challenging targets and have shown promise in a number of important areas including oncology, anti-microbial and anti-parasitic indications. We have a close collaboration with Canterbury Christ Church University and their industrial liaison laboratory, where we have a joint PhD student making progress in finding novel therapeutics for pancreatic cancer from venoms. Just last month SKY NEWS picked up on the fact that we have a collection of venoms that have a pallet of antibacterial activities. As these peptides have evolved in nature for millions of years there is a greater chance that they have already side stepped the resistance pathways and will be able to offer real solutions to drug resistant infections. Such activities are being investigated in their own merit but they may also offer novel combination therapies and prevent a return to the dark ages of infection.
Peptides as therapeutics
Peptide therapeutics are not only becoming possible but desirable. We are truly entering into an age of biologic drugs, and venoms will be part of that. Peptide chemistry is evolving along with our need for new therapeutics and is making headway into overcoming peptide therapeutics’ major challenges such as improved bioavailability and better half lives. Venoms aChoose from the most used tagslready have an advantage over other peptide therapeutics because they have evolved to be stored in glands ready for use at a moment’s notice, often in animals that don’t use them for months on end. This means venoms have an inherent stability, that is vital for any peptide to be therapeutically useful.
As a scientific community, we are still trying to piece together the complex relationship between venoms and potential human molecular targets. However, we can see the applicability of venom-derived peptides in all therapeutic areas, both as tools and as therapeutics in their own right. Our expertise in both venomous animal husbandry and venom biochemistry has delivered hits for every target our customers have challenged us with, including orphan GPCRs and tough ion channels. As we enter a new age of medical and technological innovation, we expect that venom peptides will be a greater part of the solutions for disease and that Venomtech will be at the forefront of venom-based research.