Small molecule rescues unstable mitochondrial enzyme

Cells can’t operate without the power supplied by working mitochondria. When the mechanisms that replicate or repair mitochondrial DNA (mtDNA) fail, it can cause a wide range of syndromes for which there are few to zero existing treatment options. One of the causes of these syndromes is a misbehaving mtDNA polymerase called POLG. Mutations or deletions in the gene for POLG yield defective polymerases that cannot stay on the mtDNA template, thus leaving the enzyme’s tasks incomplete.

A new small molecule, PZL-A, fixes the erring polymerase, rescuing its ability to synthesize mtDNA. Pretzel Therapeutics, a biotechnology company based in Waltham, Massachusetts, developed the molecule. The research was published in Nature on Wednesday. PZL-A works by binding to POLG and stabilizing it, helping the mutant POLG stay on the circular mtDNA longer, which in turn helps it copy and repair more of it (Nature 2025, DOI: 10.1038/s41586-025-08856-9).

PZL-A binds to an allosteric site on POLG that is conserved across the most common POLG mutants, making it a “mutant-agnostic” therapeutic option, says Gabriel Martinez, Pretzel’s chief scientific officer and cofounder.

The paper doesn’t include in vivo data, but its value comes from identifying an unusual mechanism of action and presenting a potential treatment option for damaged POLG, Martinez says.

PZL-A acts as a proof of concept for the firm’s approach. A different, more optimized version of the molecule, called PX578, has been advanced to the clinic. That compound recently entered Phase 1 trials.