Compugen: New Discovery Method for Drug Candidates That Interfere With Protein Conformations

Compugen today issued a press release (http://www.cgen.com/Content.aspx?Page=press_releases&NewsId=551), stating that it had developed a new method based upon in silico (by computer) prediction of previously unknown conformations of target proteins, facilitating the design of novel drug candidates:

"Compugen . . . announced today the development of a method to identify novel therapeutic candidates to interfere with disease associated protein conformations and protein-protein interactions. This new in silico method relies on the prediction of hidden conformations of the proteins of interest, which is the subject of a scientific paper to be published in the journal Bioinformatics . . . .

Proteins are dynamic entities and can adopt a series of different conformations. However, some of these conformations are “hidden”, since they are short-lived or difficult to study experimentally for other reasons. Since this dynamic property of proteins is important for their function in healthy and diseased states, a broad view of a protein’s conformational space is crucial in many aspects of drug discovery."

Okay, what does this mean? If you're waiting for me to tell you that it's not rocket science and readily understood by persons like myself, you're mistaken. This is rocket science. Moreover, if it wasn't rocket science, it wouldn't be worth contemplating, because, as I have often said, predictive, algorithm-driven biology, based upon the most advanced computer science, is necessary to give rise to the next generation of therapeutics.

So what can we poor laymen hope to understand from this announcement?

First, the perception of proteins and their relationship to disease continues to evolve. Although the link between proteins (e.g., in excessive quantities, in insufficient quantities) and diseased states has long been known, emphasis had been placed upon their static structures. Today, it is better understood that proteins twist, turn and fold within conformational boundaries, and some of these alternate structures cause disease.

More simply stated, proteins, for the purpose of drug development, are moving targets that can be extremely hard to hit.

And if you are seeking to cure, for example, various kinds of cancer, you are going to have to contend with these alternate states.

Compugen is now saying that it can even more accurately predict the various conformational changes in protein structure, including those that are short-lived. Moreover, as we have also learned from prior announcements, they believe that they can design the peptides that are able to interfere with protein disease-associated conformations, i.e. trap proteins in their inactive state (see: http://jgcaesarea.blogspot.com/2009/08/compugen-evolution-of-new-platform-for.html), and block protein-protein interactions which give rise to disease (see: http://jgcaesarea.blogspot.com/2010/04/compugen-molecular-locksmith.html).

The ability to:

(1) locate the "door" to a specific disease along the length of a given protein (proteins are generally between 50 and 2,000 amino acids in length and consist of 20 types of amino acids), which can assume multiple conformations, and

(2) block the "keyhole" with a custom designed peptide,

provides further evidence of the power of Compugen's cutting-edge science.

[As noted in prior blog entries, I am a Compugen shareholder, this blog entry is not a recommendation to buy or sell Compugen shares, and in mid-September 2009 I began work as a part-time external consultant to Compugen. The opinions expressed herein are mine and are based on publicly available information. This blog entry has not been authorized or approved by Compugen.]

Compugen: The Evolution of a New Platform for the Rational Design of Therapeutics

In March 2008 Compugen announced the development and validation of its Blockers of Disease Associated Conformation ("DAC Blockers") discovery platform for the identification of peptides that block proteins from adopting their disease associated conformations. A little over a year since this announcement, there have been further announcements concerning the platform's initial therapeutic candidates, CGEN-25007 for inflammatory bowel disease and CGEN-25017 for retinopathy, both of whose in vivo results are best understood from the attestations of the outside parties who performed the testing.

Re CGEN 25007:

"Professor Markus F. Neurath, from the University of Erlangen, Germany, who supervised the study and is a recognized world expert in this field stated, 'The results achieved with CGEN- 25007 are very impressive. In the past, we have evaluated numerous molecules in this model but never saw such dramatic effects. If these results continue to be confirmed in further studies, this molecule should represent a very exciting drug candidate for this substantial, and largely unmet medical need.'"

Re CGEN-25017:

"Professor John S. Penn, from the Department of Ophthalmology and Visual Sciences at the Vanderbilt University School of Medicine, who supervised the study and is a recognized world expert in this field stated, 'The efficacy achieved with CGEN- 25017 is a fairly rare finding in this model. Based upon our past experience conducting efficacy trials of this type, CGEN-25017 falls within the top 10% of all test compounds that have passed through our hands. Thus, in my opinion, CGEN-25017 warrants further development and study as a potential therapy for angiogenesis-related diseases.'"

There is nothing "hit or miss" about these discoveries. As noted by Compugen:

"To date, peptide blockers predicted by this platform have been validated experimentally in functional assays for 11 out of 12 protein targets selected for screening."

At a time when Big Pharma's pipelines are going dry, how did this new discovery platform evolve? Compugen will never disclose all of the platform's underlying proprietary wizardry. In addition, it seems inane for an "outsider" to summarize the platform's scientific underpinnings, premised upon 10 years of R&D, within the space of a blog entry, yet here is my attempt:

Proteins consist of long strings of amino acids, generally between 50 and 2,000 amino acids in length and consisting of 20 types of amino acids. The location of these amino acids determines their many possible shapes (for example, Alpha Helix, Beta Helix, turns and loops), i.e. how these proteins fold. A protein's shape, in turn, determines its function.

Although proteins normally fold into a single stable conformation, slight changes can subsequently occur within certain proteins, causing them to become active or inactive, i.e. giving rise to "disease associated conformations". The literature indicates there are dozens of such disease associated conformations potentially causing pathologies, but how do you even begin to influence these minuscule transformations, which can cause, for example, solid cancers and inflammatory diseases?

Some 10 years ago it was already known that peptides (protein fragments) could be used to seal off cells from viruses, e.g., HIV, seeking to penetrate their membranes. It was believed that peptides could similarly be used to bind to proteins at relevant sites, thereby preventing them from adopting their disease associated conformations, but it would be necessary to know the specific segment of the given protein. Compugen seized upon this idea and began to construct its platform:

"The [DAC Blockers] platform is based on the integration of methods and ideas varying from information theory, through machine learning and statistics, to mathematical analysis for detecting intra-molecular interactions within the protein of interest."

Details concerning a resultant product candidate? Let's look at CGEN-25007, which interacts with the glycoprotein, gp96. As observed in Compugen's website:

"extracellular gp96 plays an important role in activation of innate immunity, through direct action on various types of immune cells, including dendritic cells, monocytes, macrophages and neutrophils, promoting the induction of proinflammatory cytokines."

Cytokines are secreted by immune cells that encounter pathogens, thus recruiting additional immune cells to augment the body's response, which can cause acute inflamation, and the DAC Blockers platform was initially validated by Compugen by demonstrating that CGEN-25007 significantly reduces the serum levels of inflammatory cytokines in mice treated with lipopolysacharide, which acts as a toxin and causes strong immune responses. Given that gp96 has been implicated in inflammatory bowel disease ("IBD"), the next step taken by Compugen was to test CGEN-25007 on an IBD animal model. The results of the testing conducted by Dr. Neurath (see above) were announced in June:

"In a recently completed study of TNBS-induced colitis, which is a well accepted animal model of inflammatory bowel disease, administration of CGEN-25007 protected mice from the effects of lethal colitis. Study data showed an increase in survival rate and reversal of weight loss, while mice treated with a negative control showed an irreversible and fatal wasting syndrome. This protective effect of CGEN-25007 was confirmed by improved endoscopic colitis scores, which were similar to those obtained with corticosteroids as a positive control."

With respect to IBD, there are 500,000 persons in the U.S. suffering form Crohn's Disease and another 5 million persons suffering from Irritable Bowel Syndrome. We will see whether Compugen now also tests CGEN-25007 on an in vivo model of rheumatoid arthritis, which affects some 1% of the world's population and for which there is no known cure.