Venoms to Drugs

At Atheris labs we have spent several years investigating natural compounds from a variety of venomous organisms and other natural sources. We have patiently built a unique, world-class expertise pertaining to the extraction, isolation, purification, characterization and synthesis of bioactive compounds.

Our original strategy for the discovery of novel bioactive compounds is based on a judicious combination of our Venoms databases, Melusine collections and unique know-how. It involves:

• Biocomputing-assisted sample selection and follow-up.
  
  
• MELUSINE libraries for high throughput screening (HTS).
  
  
• Bioactivity-guided fractionation and hit isolation.
  
  
• Structure-driven deconvolution and lead selection.
  
  
• Validation on synthetic analogue.
  
  
• Lead selection based on multiple key parameters.
  
  
• Intellectual property evaluation and patent application.
  
  
• Lead optimization through natural analogues and drug design.
  
  
• Early development including PK-ADME studies.
  
  

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Love At The First Sting ?

With more than 100'000 species, venomous are spread towards the whole animal kingdom phyla. Venoms are highly concentrated and complex fluids. Each individual venom can contain from 100 to more than 1'000 potent and selective bioactive compounds such as: Proteins, Toxins, Peptides, and other smaller chemical entities. When injected into living organisms a few droplets of venom can induce devastating damage within seconds. Hence the two questions and a major motivation for our research activities:

WHAT IS THERE IN SUCH A SMALL DROPLET THAT CAN CAUSE SUCH DAMAGE ?

HOW CAN WE TURN THIS IMPRESSIVE DESTRUCTIVE POWER OF VENOMS
INTO LIFE-SAVING DRUGS ?

Atheris specializes in the study of their in vivo behavior and in the direct analysis of crude venoms. The discovery of naturally occurring bioactive compounds usually relies on the initial observation of a particular biological activity of a crude extract, which is followed by purification and structural characterization.

We have developed several novel approaches for direct analysis of crude venoms using mass spectrometry (on-line LC-ESI-MS, MS/MS and MALDI-TOF-MS) in conjunction with related micro- or nano-technologies, which we couple to proprietary in silico bioinformatic tools. Our approach provides a unique fingerprint of each sample for species determination, detection of new compounds (sometimes in a single step directly from the raw venom), and batch controls prior to medical use.

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Venoms database

VENOMS, our proprietary database contains a wealth of information over more than 2’000 described venomous animals, more than 3'500 toxins and enzymes, 3'000 antimicrobial peptides and over 300’000 bibliographical references in the field of venomous animals and their venoms.

The files also cover hundreds of mass fingerprints of raw venoms, clinical data, all related intellectual property and technology surveys. Our unique methodology allows us to undertake extremely focused discovery programs, in a cost- and time-effective manner.

Go to Venoms database for additional information on our methodology.

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Melusine collections

In April 2008, Atheris launched a new concept in the form of a product. Melusine is a unique collection of animal venoms, insect hemolymphs and other natural extracts, each pre-fractionated and made ready in microplates as natural libraries for high-throughput screening assays (HTS).

Furthermore, Atheris possesses its own library of purified natural and synthetic bioactive peptides and proteins that are of relevance to diseases affecting the Nervous, Cardiovascular, Gastro-Intestinal, Hormonal, Immune and Respiratory systems.

Using its own discovery tools and resources, and in collaboration with industrial and academic partners, Atheris aims to contribute to the development of new bioactive ingredients such as drugs, cosmetic agents, nutraceuticals, diagnostic and research tools.

Visit Melusine web pages for additional information on our methodology.

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Peptide drugs

The recent advances in combinatorial chemistry inflated the number of available chemical libraries of compounds from a few hundred thousands to many millions. At the same time, the completion of the Human Genome Project has led to the identification of a plethora of potential targets for screening efforts and subsequent validation. To cope with the ever-increasing demands of target discovery, most pharmaceutical companies use High Throughput Screening to screen large libraries of compounds against potential targets. Whilst this powerful screening approach has led to satisfactory results, there are certainly opportunities to add some intelligence into the process in an attempt to gain in efficiency.

This can be achieved through a judicious selection of libraries of molecules selected and further improved by original strategies we like to use to adress such needs, mainly by using natural libraries.

Microbials, plants and animals produce a huge array of biologically active peptides and proteins, including those found in venoms. They act as defensive tools against predators, infection and overgrowth, but are also used for prey acquisition. These compounds pose serious health problems to humans, but they can also offer huge benefits if used appropriately. Venom components are indeed extremely potent and selective, making them a unique source of inspiration to discover novel drug candidates.

While common peptides are known to be very selective, specific and poorly toxic, they have a few drawbacks: Their half-life is short, delivery and solubility are often challenging and the costs of goods tend to be high.

Venom derived peptides and proteins avoid most of these drawbacks, even transforming them into advantages: they are extremely resistant to proteases, thus stable and offering prolonged half-lifes. They are highly soluble and poorly immunogenic, often folded in a very efficient manner.

Last but not least, their extreme selectivity and potency at nanomolar or even picomolar concentrations makes the cost of goods on a "per dose" basis extremely competitive when compared to other drugs on the market.

They have an excellent "drugability" potential and also offer very nice structural backbones for drug design, which has already led five venom derived drugs to reach the market. These success stories are:

• Aggrastat® (tirofiban) from Merck Co, Inc; a RGD peptide analogue from viper venom anticoagulants to treat angina.
  
  
• Byetta® (exenatide) from Amylin Pharmaceuicals, Inc; a GLP-1 analogue from the Gila monster venomous lizard for diabetes.
  
  
• Capoten® (captopril) from Bristol-Myers Squibb Company; a blockbuster drug (angiotensin converting enzyme inhibitor) from a Brazialian lancehead snake to treat hypertension.
  
  
• Integrilin® (eptifibatide) from Millennium Pharmaceuticals, Inc; a KGD peptide from rattlesnake venom as anticoagulant.
  
  
• Prialt® (ziconotide) from Elan Corporation, plc; an ion channel modulator for severe chronic pain from the Conus magus venomous cone snail.
  
  

And there are many more to come and we hope to be part of these adventures!

Go to Lead discovery for additional information on our methodology.

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