PNC-27, a Chimeric p53-Penetratin Peptide Binds to HDM-2 in a p53 Peptide-like Structure, Induces Selective Membrane-Pore Formation and Leads to Cancer Cell Lysis

  • Biomedicines. 2022 Apr 20;10(5):945. doi: 10.3390/biomedicines10050945.
Ehsan Sarafraz-Yazdi  1 ,  Stephen Mumin  1 ,  Diana Cheung  2 ,  Daniel Fridman  2 ,  Brian Lin  2 ,  Lawrence Wong  2 ,  Ramon Rosal  3 ,  Rebecca Rudolph  4 ,  Matthew Frenkel  4 ,  Anusha Thadi  5 ,  William F Morano  5 ,  Wilbur B Bowne  5  6 ,  Matthew R Pincus  2 ,  Josef Michl  2
Affiliations
  • 1. NomoCan Pharmaceuticals LLC, New York Blood Center, 310 East 67th Street, New York, NY 10065, USA.
  • 2. Department of Pathology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
  • 3. Department of Health of New York City, 455 First Avenune, New York, NY 10016, USA.
  • 4. Microscopy and Imaging Department, American Museum of Natural History, Central Park West and 79th Street, New York, NY 10024, USA.
  • 5. Department of Surgery, Drexel University College of Medicine, 230 North Broad Street, Philadelphia, PA 19102, USA.
  • 6. Department of Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, 1100 Walnut Street, Philadelphia, PA 19107, USA.
PMID: 35625682 DOI: 10.3390/biomedicines10050945
Abstract

PNC-27, a 32-residue peptide that contains an HDM-2 binding domain and a cell-penetrating peptide (CPP) leader sequence kills Cancer, but not normal, cells by binding to HDM-2 associated with the plasma membrane and induces the formation of pores causing tumor Cell Lysis and necrosis. Conformational energy calculations on the structure of PNC-27 bound to HDM-2 suggest that 1:1 complexes form between PNC-27 and HDM-2 with the leader sequence pointing away from the complex. Immuno-scanning electron microscopy was carried out with Cancer cells treated with PNC-27 and decorated with an anti-PNC-27 antibody coupled to 6 nm gold particles and an anti-HDM-2 antibody linked to 15 nm gold particles. We found multiple 6 nm- and 15 nm-labeled gold particles in approximately 1:1 ratios in layered ring-shaped structures in the pores near the cell surface suggesting that these complexes are important to the pore structure. No pores formed in the control, PNC-27-treated untransformed fibroblasts. Based on the theoretical and immuno-EM studies, we propose that the pores are lined by PNC-27 bound to HDM-2 at the membrane surface with the PNC-27 leader sequence lining the pores or by PNC-27 bound to HDM-2.

Keywords
HDM-2/MDM-2; PNC-27; cell-penetrating peptides (CPP); p53 binding domain; plasma membrane pore formation.
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