PZL-A

**PZL-A** is a first-in-class small-molecule activator of mitochondrial DNA (mtDNA) synthesis discovered through a high-throughput screen of 270,000 compounds by Pretzel Therapeutics in collaboration with University of Gothenburg researchers. It binds allosterically at the interface between the catalytic POLγA subunit and accessory POLγB subunit of DNA polymerase γ (POLγ), stabilizing their interaction, enhancing nucleotide incorporation rate (k_cat), processivity, and template DNA binding without impairing proofreading exonuclease activity. This restores near wild-type POLγ function across multiple disease-associated mutants (e.g., A467T, G848S, R232H, W748S), boosts mtDNA replication and repopulation in patient-derived fibroblasts and neural stem cells even under nucleotide limitation, increases mitochondrial gene expression, oxygen consumption, OXPHOS activity, and ATP production. PZL-A is a potent research tool compound (AC50 20–200 nM) structurally similar to Pretzel's clinical candidate PX578 (Phase 1 in healthy volunteers), primarily targeted at POLG-related mitochondrial DNA depletion syndromes (MDDS) with potential expansion to neurodegeneration and aging.[1][2]

Other names

Compound 1Compound1Compound-1