Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Companies are taking aim at otherwise untractable targets.

Innovations to enhance the performance of peptide therapeutics continue to evolve as they attract more development deals. Changes have occurred in peptide chemistry, formulation, synthesis, manufacturing, and delivery. Peptide fans say they have multiple advantages compared to small molecule drugs, including relatively high activity, specificity, and potency as well as lower toxicity.  Drawbacks that peptide companies are working to overcome include low bioavailability, instability, poor solubility, delivery challenges, and manufacturing costs.

Innovations in peptide structure include Anchor Therapeutics’ pepducin technology, which has demonstrated the ability to prevent breast cancer, blood clotting, and sepsis in animal models. On August 20, the company drew $10 million in a Series B financing. On September 9, Ortho-McNeil-Janssen Pharmaceuticals signed on to use pepducin technology to develop GPCR-targeted therapeutics for oncology and metabolic disorders. Anchor will receive an up-front payment as well as research support and could be eligible for development and regulatory milestone payments of up to $480 million. 

Pepducins are short peptides containing a lipid moiety. This allows them to bind to the intracellular portion of receptors and change their conformation, a process known as allosteric modification, unlike classical ligands that bind to the extracellular surface of receptors. Pepducins were developed in the late 1990s by Athan Kuliopulos, M.D., Ph.D., and his colleagues at Tufts University Medical Center.

“Because pepducins can penetrate the cell and can either agonize or antagonize their targets, they are a potent tool both for research and therapeutic applications,” Dr. Kuliopulos explained. “Pepducins can greatly increase both the range of tractable targets and the specificity with which we can modulate their effect.”


Over 100 of the 700 GPCR proteins encoded in the genome have known or presumed therapeutic potential but have escaped targeting due mostly to their inaccessible location on the intracellular face of cell membranes, according to Dr. Kuliopulos. While diverse in their primary amino acid sequences and functions, all GPCRs share a highly conserved spatial configuration.

GPCR proteins consist of three different subunits (heterotrimers) consisting of  a seven-transmembrane helical core domain held together by three intracellular loops, three extracellular loops, and N- and C-terminal domains that span the entire cell membrane.

Key to changing the receptor from inactive to active are ligand-induced conformational changes of transmembrane helices 3 (TM3) and 6 (TM6). These helical movements in turn change the conformation of the intracellular loops of the receptor to promote activation of associated heterotrimers. 

“Most people are looking for molecules, particularly small molecules that will engage the binding site for GPCR that is on the outside of the cell. We focus on a site on the opposite side of the receptor, inside the cell membrane,” Anchor’s president and CEO, Frederick Jones, M.D., explained to GEN.

“We create peptide libraries based on the exposed areas of the intracellular GPCR loops to find peptides that act as mimics and compete with the loops that they are modeled on. These peptides can change the normal interactions among the loops. For example, preventing the shape change may make it more difficult for the ligand to signal, thereby downregulating signaling, while facilitating the shape change upregulates receptor activity.”

Dr. Kuliopulos’ team has shown that pepducins activate or inhibit a class of GPCRs, protease-activated receptors (PARs), that play key roles in thrombosis, inflammation, and vascular biology.

CXCR4 Receptor

Additionally, Dr. Jones told GEN that Anchor is close to identifying a development candidate that acts as an agonist for the CXCR4 receptor, a receptor on bone marrow stem cells that, when activated, promotes their sequestration within the bone marrow through its interaction with the SDF1-α ligand.

Drugs that block the CXCR4 receptor allow hematopoietic stem cells to exit the bone marrow and move into the bloodstream, where they can be harvested for eventual reinfusion as part of an autologous stem cell transplantation procedure.

“We can use our agonists to set up high local concentrations of this ligand, for example, to concentrate stem cells at a site of injury in the body and have shown that we can mobilize stem cells from the bone marrow to come to the injured site, taking advantage of the body’s stem cells without the need to harvest the cells.”

In particular, he says, Anchor is interested in post-infarction left ventricular injury, bone injuries such as osteoporotic fractures or avascular necrosis, or bone allograft incorporation.  The company hopes to file its first IND in 2012.


Also revamping peptide structures for therapeutic applications is LipimetiX, which was formed in April with rights from the University of Alabama to two preclinical drug candidates. The licensed compounds mimic the structure and function of the receptor binding and lipid binding domains of apolipoprotein E. The peptides, because of their structures, can insert into lipid-rich lipoproteins and direct them to receptors on the liver, where they are internalized and degraded, thereby decreasing blood cholesterol levels.

The company’s two lead product candidates, AEM-28 and AEM-18, have demonstrated selective non-HDL cholesterol clearance, excretion of excess cholesterol, and rapid restoration of vasorelaxation in    animal models, according to the company. 


Another peptide in development with a novel structure is Hematide (peginesatide), but the drug recently triggered some safety issues in Phase III testing. In June Affymax and Takeda Global Research & Development Center reported preliminary results for Hematide in the treatment of anemia in chronic renal failure patients. Affymax’ shares fell 69% after the company released the disappointing results.

Hematide, a pegylated synthetic peptide-based erythropoietin agonist, binds to and activates the erythropoietin receptor and thus acts as an erythropoiesis stimulating agent (ESA). While the peptide proved as good as Amgen’s Epogen and Aranesp in hitting the study’s primary endpoint of maintaining hemoglobin levels in chronic renal failure patients, it also produced some concerns about its cardiovascular safety in the nondialysis patient group.

When a subgroup analysis of the trial results was conducted, 22% of nondialysis patients taking Hematide had a cardiovascular complication, compared with 17% of those taking Aranesp. The biggest difference was seen in the number of patients who died of a heart-related problem: 8.8% among the Hematide users compared with 6.7% of those taking Aranesp.

Marching into the Clinic

Pioneers in the field have different opinions about what has impeded therapeutic development.  “Peptides come in and out of favor about every 10 years,” Richard Houghten, founder and president of Torrey Pines Institute for Molecular Studies, told GEN.

In general it seems that optimism trumps disappointment. To date, 54 therapeutic peptides have been marketed worldwide, with 26 of these in the U.S., according to the Peptide Therapeutics Foundation. And four U.S.-approved peptides reached over $1 billion in global sales.

Dr. Houghten also noted that once peptides make it to the clinic, they enjoy a higher rate of success than small molecule drugs. And it looks like the every ten years has come around again. According to the Tufts Center for the Study of Drug Development 2010 report on the state of the therapeutic peptide field, the number of new peptides entering clinical testing doubled in the past decade.

The Tufts Center found that of the 334 peptides known to have undergone some clinical testing by commercial firms, half entered the clinic in the last decade. There has been an average of about 17 new clinical candidates in each of the last 10 years compared to fewer than 10 in the decade before that and under five in the 1980s.

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

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