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.
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.