Drug discovery: Excersized rats live longer and stapled peptides last longer!!
Had a chance to listen to another couple of interesting talks this week.
The first one was by Dr. Konstantin Khrapko from the Harvard medical school, talking about the somatic mutations of mitochondrial DNA. I have to admit that I have almost no experience in his field of mitochondrial DNA research. Apparently, the mitochondrial DNA (mDNA) present in each mitochondria, in each cell, undergoes a number of mutations over our lifetime and they influence a number of physiological functions. The mDNA have almost no DNA repair mechanisms unlike the nuclear genomic DNA. Hence, large number of mutations get accumulated over time and cause age-related diseases. One of the interesting phenomenon that Khrapko and others in the field have observed is that these mutations are identical in all mitochondria in the same cell (or bunch of cells risen from the same mother cell) indicating a common source and a quick spread. They are not sure about how the initial mutation/deletion gets transmitted to the others, but this can be measured pretty accurately now.
Logic would dictate that mtDNA mutations, when present at levels lower than in phenotypically normal Polgmut/+ mice (dashed green line), are irrelevant for aging. However, in aged human colon, the typical histological pattern of mitochondrial defects (blue crypts in the inset) associated with increased mtDNA mutant fractions in individual crypts suggests otherwise15. Fractions in colon include clonally expanded mutants only. Error bars represent estimated variation of the data. Figure provided by L. Greaves and D. Turnbull (University of Newcastle).(Source: Mitochondrial DNA mutations and aging: a case closed?Konstantin Khrapko & Jan Vijg Nature Genetics 39, 445 - 446 (2007))
So how does this affect the rest of us not working in this field? Well, when they developed a rat model by causing similar mutations/deletions in the mDNA of fertilized eggs, the offsprings grow old and diseased rather quickly!! This rapid aging with features including, muscle loss, har loss, greying of hair, CNS disorders, poor metabolism etc is rather clear from the pictures of these rats. The rather more interesting observation was that when these rats were made to exercise (since birth), they avoided this prognosis completely and were indistinguishable from the regular rats!!
So what does all this mean? Well they are still trying to figure it out. I don't know about you but In the meantime, I would help myself to a healthy serving of exercise in the hope that it will extend my lifespan!
The second talk was by Dr. Tomi Sawyer from Aileron Therapeutics on the development of stapled peptides and how this work led to a $1.1 billion aggrement with Roche! I am sure most of you readers are familiar with the fact that peptides are an excellent alternative to small-molecule drugs due to their specificity and 'easy' development. But, one of the major drawbacks since their develpoment a couple of decades ago has been their poor stability in the gut and in the plasma. One of the novel methods that Aileron have used to stabilize these peptides is by "stapling" these peptides using chemical linkers. This not only improves their stability as a peptide but is also able to hold the peptide in the form of a alpha helix thus enabling their use in protein-protein interaction modulations.
One of the targets they have been working on for Roche is the MDM2 and MDMX dual-targeting alpha-helical peptides as an anti-cancer therapy. These stabilized peptides can interact with both MDM2 and MDMX proteins, with good affinity, and prevent their interaction with p53. This allows p53, a pro-apoptotic protein, to kill the cancerous cells. Although I was familiar with this strategy from the FierceBiotech's coverage of their recent Phase I trial success, I did not realise that some of these peptides have a plasma half-life of around 24 hours!! This obviously makes it a very interesting drug design strategy to watch out in the near future.
