To trip up fast-proliferating cancer cells, try throwing a wrench in their proliferation machinery, the aptly named proliferating cell nuclear antigen (PCNA). Wielding a new kind of wrench, a drug-like protein called a peptidomimetic ligand, scientists based at the University of Adelaide have jammed PCNA more effectively than scientists who have deployed more conventional drugs.

The scientists, led by John Bruning, Ph.D., structural biologist at the University of Adelaide, say that their drug-like protein is unlikely to provoke resistance because PCNA seldom mutates. The scientists add that inhibiting PCNA, which is also known as the sliding clamp, is an especially promising anticancer approach because PCNA is overexpressed in 90% of all cancers. In other words, the drug-like PCNA inhibitor could be used to treat multiple cancers, not just a select few.

The structure-guided design of the drug-like PCNA inhibitor is described in a recent article (“Rational design of a 310-helical PIP-box mimetic targeting PCNA—the human sliding clamp”) that appeared in the journal Chemistry—A European Journal. As this article indicates, Dr. Bruning and colleagues focused on a conserved peptide motif known as the PCNA-interacting protein box (PIP-box). Essentially, the scientists decided to inhibit the protein-protein interactions by which the PIP-box recruits proteins to the PCNA surface.

These interactions are essential to the operation of the PCNA, which completely encircles DNA at the double helix’ replication fork. PCNA also binds to DNA polymerase, which is constrained by PCNA to slide along a template DNA strand, adding nucleotides to a new, and growing, DNA strand.

To create a PCNA inhibitor, the University of Adelaide team rationally designed and synthesized what it asserts are the first PCNA peptidomimetic ligands. These ligands, the team reports, are based on the high-affinity PIP-box sequence from the natural PCNA inhibitor p21.

“These mimetics incorporate covalent i,i+4 side-chain/side-chain lactam linkages of different lengths, designed to constrain the peptides into the 310-helical structure required for PCNA binding,” the authors wrote. “NMR studies confirmed that while the unmodified p21 peptide had little defined structure in solution, mimetic ACR2 pre-organized into 310-helical structure prior to interaction with PCNA.”

ACR2, the authors added, displays higher affinity binding than most known PIP-box peptides, and retains the native PCNA binding mode, as observed in the co-crystal structure of ACR2 bound to PCNA.

“If we can inhibit the action of this protein, the cells can't make DNA, so they can't divide,” explained Dr. Bruning. “This is really tackling cancer at ground zero. It's stopping cell division and therefore tackling cancer at its most fundamental level.”

“In this study, we have taken a protein fragment that naturally interacts with PCNA and transformed it using smart chemistry into a drug-like molecule,” added lead author Kate Wegener, Ph.D., a research fellow at the University of Adelaide. “We've changed its chemistry to protect it from degrading like the natural protein, and so that it works better.”

The new molecule shows increased potency over other PCNA inhibitors, and it is likely to show fewer side-effects.

“Because of the special approach we have used in turning a natural protein into a drug-like molecule, it fixes to PCNA more readily and its action is specific to this protein,” asserted Dr. Bruning. “This is a first. It's the first in this type of inhibitor and it will pave the way for a new class of drugs inhibiting the proliferation of cancerous cells.”

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