Aileron Staples Peptides

Abstract

DOI 10.1016/j.chembiol.2009.09.008Existing drugs can be roughly classifiedeither as biologics or small molecules.Biologics include antibodies or insulinthat does not penetrate into cells, whichlimits their target range, as <10% ofhuman proteins are found on cellsurfaces or are secreted. Although ableto penetrate cells, small molecules havelimitations of their own. ‘‘The entirebiotech industry has been working on10% of human targets,’’ said GregoryVerdine, Ph.D., Erving professor ofchemistry, Harvard University. ‘‘Smallmolecules only work on proteins thathave a specific feature on their surfaces.That is another 10% of all human targets.So that means 80% are not approach-able by the two established modes ofdrugs.’’Wielding the Chemical Staple GunVerdine and Cambridge, MA, based Aile-ron Therapeutics (http://www.aileronrx.com) believe that they have found thekey to accessing this so-far untappeduniverseoftargets.Proteins,throughtheirsubdomains, play a role in almost everycellular process in the body; however,subdomain-derived peptides have beendifficult to turn into drugs. Because theylack defined structure, these peptidesare quickly degraded by proteases andare dispatched by the kidneys. Currently,there are more than 40 peptide drugs onthe market, such as Amylin’s Byetta, ana-helical peptide treatment for diabetes,but the drugs target receptors on thecells’ surfaces.Aileron Therapeutics stabilizes pep-tides by ‘‘stapling’’ them with hydro-carbon bonds into an a helix, a structurepeptides can naturally assume in pro-teins. Thus constrained in a helical forma-tion, the peptides are protected from thedepredations of proteases. The stabilizeda-helical peptides can penetrate cells byenergy-dependent active transport andusually have a higher affinity to largeprotein surfaces.The company believes its stapleda-helical peptides have wide therapeuticpotential for cancer, autoimmune, inflam-matory, infectious, and metabolic dis-eases. Aileron was started in 2005 byCEOJosephYanchik,III,usingIPlicensedfrom Verdine at Harvard and cofoundersLoren Walensky, M.D., Ph.D., assistantprofessor of pediatrics, and the lateStanleyJ.Korsmeyer,M.D.,SidneyFarberprofessor of pathology and professor ofmedicine, at the Dana-Farber CancerInstitute and Harvard Medical School.Aileron Therapeutics is funded bythe investment arms of four pharma-ceutical companies. In June 2009, itannounced a $40 million D fundinground from Apple Tree Partners, SROne,Ltd. (GlaxoSmithKline), Excel MedicalFund, Novartis Venture Fund, LillyVentures, and Roche Venture Fund.Breaking Down Barriersfor a-Helical PeptidesChemically constraining peptides intoa helix has challenged researchers fordecades. Verdine’s lab applied the cata-lyst developed by Nobel laureate RobertGrubbs, Ph.D. at CalTech. ‘‘We knewthat a helices were frequently involved inmediating protein-protein interactions,’’Verdine said. ‘‘We also knew by maxi-mizing helix stability we would solve theproblem of proteolytic degradation. Noprotease can recognize an a helix.’’ But,according to Verdine, stabilized a-helixpeptides previously developed by otherresearch labs did not penetrate cells.To stabilize peptides, Verdine and hispostdoc Christian Schafmeister, Ph.D.(now associate professor, Department ofChemistry, Temple University) used anolefin metathesis reaction. They drewupon the work of Isabella Karle, Ph.D,the former chief scientist at the Office ofNaval Research, X-Ray Diffraction Sec-tion, who showed that adding a methylgroupstothepeptidescouldlocallystabi-lize the rings of the helix, and of PeterSchultz, Ph.D, professor of chemistry,Scripps Research Institute, who showedthat macrocycle rings connecting adja-cent turns of the helix created a globalstabilizing effect. Staple placement alsomattered.Proteins can’t penetrate a cell wallbecause they have too many polar atomsand are generally hydrophilic, thus, theyare incompatible with the hydrophobicinterior of the membrane. This led to theidea that the macrocycle ring should beall hydrocarbon. ‘‘We didn’t want anyatoms to impede cell penetration,’’ saidVerdine. Loren Walensky, then a postdocinVerdine’slab,discoveredthatthestabi-lized cell helices didn’t penetrate the cellvia passive diffusion, but by active endo-somal uptake. ‘‘That was a serendipitousbut very, very important discovery,’’ saidVerdine. ‘‘What is so great about it isthat it has broad applicability to a widevariety of peptides.’’According to Verdine, bioavailabilitywas another hurdle. For instance, whenantisense oligonucleotides are taken upinto the cell by endosomal trafficking,they can’t get out of the endosome; how-ever,stapledhelixesareexcellentescapeartists. For example, the cell’s nuclearenvelop blocks passage of anything over25 kDa, but allows smaller moleculesthrough. Stapled a-helical peptides aresmall enough to access targets in thenucleus and in the cytoplasm. The syn-thetic peptides have a similar bindingspecificity to the protein from which theywere derived.Playing Cell Guardiansand Executioners Off Each OtherLoren Walensky’s laboratory is develop-ing new strategies to study and treat