Discovery of small PEDF peptides that promote photoreceptor survival

Authors

• A Hernandez-Pinto
• P Subramanian
• SP Becerra

Abstract

PEDF is a multifunctional protein with neurotrophic, antiangiogenic, antitumorigenic, antimetastatic and antiinflammatory properties. Structure-function relationships have revealed two distinct regions on the PEDF polypeptide for neurotrophic and antiangiogenic activities. Given its multimodal nature, fragmentation of PEDF protein is ideal to study individual activities and develop agents relevant for use in the clinic. Recently we found a short fragment of 17 amino acids within the neurotrophic region of PEDF that has affinity for PEDF receptor PEDF-R. Alanine scanned fragments revealed amino acid positions that play a role in interacting with PEDF-R for cell survival. The purpose of the study is to identify peptides from PEDF with protective properties for the retina. The retinoprotective effects of PEDF fragments were tested in retina cultures. The 17mer peptide decreased the TUNEL positive nuclei number on retina precursor R28 cells in culture and on photoreceptors of zaprinast-induced photoreceptor death in retina explants ex vivo cultures. Altered 17mer peptides with diminished affinity for PEDF-R exhibited attenuated cytoprotective effects, while peptides with higher receptor affinity had enhanced survival activity on R28 cells and in zaprinast-induced photoreceptor death in ex vivo cultures, relative to unmodified 17mer. We conclude that short peptides from the receptor binding region of PEDF retained photoreceptor protective properties of PEDF and those with enhanced activity may prove useful for the development of therapeutic agents for the protection of photoreceptor cells.

Scientific Focus Area: Molecular Biology and Biochemistry

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