PNC-27

PNC-27 is a 32-residue chimeric peptide (PPLSQETFSDLWKLLKKWKMRRNQFWVKVQRG; C188H293N53O44S, about 4,032 g/mol). It combines an HDM-2 (MDM2)-binding domain corresponding to residues 12 to 26 of p53 with a penetratin-derived cell-penetrating leader sequence. Structural analysis indicated that the three-dimensional structure of the p53-derived residues in PNC-27 is directly superimposable on the conformation of the same residues when bound to HDM-2, which led investigators to propose HDM-2 as the peptide's membrane target.

PNC-27 in the research literature

Cell-culture research on PNC-27 has examined its interaction with HDM-2 at the plasma membrane. Investigators reported significant levels of membrane-associated HDM-2 in a variety of transformed cell lines but not in several untransformed lines, colocalization of PNC-27 with membrane-bound HDM-2, and selective membranolysis of the transformed cells. Untransformed MCF-10-2A cells became susceptible after transfection with membrane-localized full-length HDM-2.

Later work proposed that PNC-27 and HDM-2 form 1:1 complexes, and immuno-scanning electron microscopy showed gold-labeled peptide and HDM-2 in ring-shaped structures within membrane pores; no pores formed in untransformed fibroblasts. An antibody against the p53-binding site of HDM-2 (residues 1 to 109) blocked the peptide's membrane activity, and immuno-electron microscopy placed the peptide on mitochondrial membranes. In transformed myeloid cell lines with high membrane HDM-2 expression, the peptide induced lactate dehydrogenase release within four hours.