Scientists at Polyphor (www.polyphor.com) spent the last decade developing protein epitope mimetics (PEM) technology to discover and optimize therapeutically valuable inhibitors of protein-protein interactions. At the conference, Daniel Obrecht, Ph.D., discussed how the company’s method generated a potent CXCR4 inhibitor.
PEM molecules aim to act as small molecules. They are fully synthetic, peptide-like molecules that mimic b-hairpins because b-hairpins often contain residues essential for protein-protein interactions. Once identified, a chosen b-hairpin is stabilized on a proprietary template. Then, focused libraries are designed around it using a multiparallel synthesis technology, and promising mimetics are optimized to the desired biological and pharmacological properties using the required design variables.
Michael Altorfer, Ph.D., CFO at Polyphor, noted the many advantages of its approach. First, he said, the “constant methodology leads to rapid improvement, eliminates repeated process development, and reduces the lead-throughput time and necessary resources. The high degree of automation increases throughput, reduces throughput time, and facilitates scalability.
“The versatile methodology permits rapid optimization of ADMET properties and selectivity, the main reasons for small molecule attrition.” Moreover, this technology is “applicable to a wide range of targets and therapeutic applications” and has the potential to “yield a new class of drugs combining the advantages of both small molecules and biopharmaceuticals.”
PEM molecules have been particularly effective at targeting GPCRs. Few small molecule antagonists of these receptors are known, perhaps because of their large ligand-binding domains. CXCR4 is a coreceptor, along with CD4, for the entry of T-cell line-tropic (X4) HIV-1 into T cells.
One of the first CXCR4 antagonists to be described is polyphemusin II, from the American horseshoe crab (Limulus polyphemus). Using Polyphor’s parallel combinatorial synthesis, Dr. Obrecht’s group developed a mimetic based on polyphemusin II but with significantly improved plasma stability, selectivity, and pharmacokinetic properties.
This CXCR4 inhibitor is currently in Phase I trials, and Dr. Altorfer is hopeful that “if these results are positive, other applications such as multiple dose treatment, e.g., neutropenia and leukemia, can be envisaged.”
These different technologies all take various tracks toward achieving similar ends—interrupting protein-protein interactions. The ends, though, are not really similar; each interaction is unique and thus might require a unique structure or mechanism to disrupt it. All of the existing technologies and maybe more are therefore necessary, and hopefully all of them will be successful.