Stapled Peptides: Twisting the Energy Away
by David Singleton on Thu April 7 2011 12:22 pm BST
Peptides and proteins are nature’s way of controlling your biochemistry. Peptides regulate your hunger and metabolism, your body temperature, pain regulation, your brain’s circuitry and even human reproduction. Peptides are natural hormone ligands for their cognate receptors binding with exquisite specificity and high efficiency because these molecular keys fit their locks absolutely perfectly.
Drug discovery researchers are now looking at molecules other than the typical, small molecule effectors we are so familiar with. The days of the blockbuster pill are numbered: Binding pockets must be set up perfectly in the receptors and, without very tight interactions with a receptor; high efficacy becomes difficult to achieve. Doses escalate from a few milligrams to higher amounts leading to off-target effects and toxicity. Small molecule drugs are excellent in oral dosing, bioavailability and crossing cell membranes and being transported in and out of their environments to do their jobs. They are inexpensive, have high stability and familiar to all patients.
Biologics such as protein and antibody therapeutics are at the other end of the spectrum. Large macromolecules can effect protein-protein interaction targets with very large binding and irregular binding surfaces. They are based on natural ligands and need little structural modification for efficacy. Dosing and pharmacokinetics and metabolism (where a drug goes and how long it lasts in that condition) are difficult and solved with injectable or highly technical dosing solutions. Drugs like Enbrel, Herceptin, and Epogen all are examples of antibody therapies made using recombinant DNA technology. These drugs are somewhat unstable, injectable only and quite expensive therapies used only when other approaches are exhausted.
These two classes are only 10% each of the chemical space which drugs might exist. The remaining 80% remains between the very small and very large molecules. As presented by Greg Verdine at the 240th National American Chemical Society meeting, somehow, this massive area needs to be explored for new therapies in disease cure and prevention[i]
Crossing the bridge between these are peptides. Peptides are smaller than proteins (although no hard and fast rule exists how much so) and can behave like small molecule drugs. They have high affinity for their receptor and have been designed so they don’t cross react with other targets. Their downfall can be absorption (like protein and antibody drugs) and half-life in the body. Insulin, GLP-1, salmon calcitonin and others have entered the market as viable alternatives in this space[ii]. Yet, like proteins, they need to be injected (or highly formulated), can be cleared and processed quickly and don’t easily cross cell membranes to reach their receptors.
Promise, as reported by Verdine, Sawyer, Walensky and others, comes from stapled peptides[iii]. Regular peptides need to bind to their receptors in exact fashion by adopting a specific structure. However, they are floppy, random, coiled or unordered and need to overcome this entropy by raising their binding energy to fit the receptor’s requirements. By “stapling” these, one can force the peptides to adopt specific conformations and overcome that entropy factor allowing tight binding. Another consequence is that the peptides are less visible to destruction and clearance via natural clearance processes. They also, in some cases, have the ability to cross cell membranes and be transported to their receptors. To see the dramatic effect stapling can have, check out this video showing just how much energy savings stapling provides on the peptide and how the binding residues line up for presentation (and the great techno music)[iv].
These rigidified peptides have been explored for decades using different approaches. Di-sulfide knots are nature’s way of making a peptide tightly folded.[v] I to i+4 cyclic lactams are similar to the stapled peptides, but require complex solid phase chemistry to prepare[vi]. Helix inducing caps have been synthesized to attempt to induce an environment where the αhelix is the strongly preferred conformation.[vii] Stapled peptides give chemists the ability to induce this helical constraint in the last step of synthesis after purification and analysis of a linear material. This highly selective clipping by either metal catalysis or photoinduction is highly selective, so the chemist has the ability to make well characterized and purified molecules through the whole process[viii].
Successes are starting to roll out. Aileron Therapeutics is based on this technology[ix] and has 3 demonstrated successes in R&D. Chemistry different from the original cyclization has opened more routes to helix induced peptides.[x]
Such elegant chemistry requires expert hands. Experience in peptide and organic chemistry syntheses give higher success rates. CRB has PhD level organic synthesis and peptide chemists for synthesizing such peptides, as well as any needs for un-natural amino acids, novel amino acids or highly complex structures. If you’re interested in peptide drugs or peptide projects which could use a burst of advancement, please contact us for more information.
- http://tinyurl.com/479lvfl
- http://qjmed.oxfordjournals.org/content/92/1/1.full
- http://pubs.acs.org/cen/coverstory/86/8622cover.html
- http://www.youtube.com/watch?v=WScPbvUwDno
- http://www.ncbi.nlm.nih.gov/pubmed/7576659
- http://onlinelibrary.wiley.com/doi/10.1111/j.1399-3011.1998.tb00664.x/abstract
- http://www.ncbi.nlm.nih.gov/pubmed/11603974
- http://tinyurl.com/4vl5tqo
- http://www.aileronrx.com/index.php
- http://www.innovations-report.com/html/reports/life_sciences/techniques_stapling_peptides_spur_development_drugs_169828.html
