title: Enantiomer-specific bioactivities of peptidomimetic analogues of mastoparan and mitoparan: characterization of inverso mastoparan as a highly efficient cell penetrating peptide.
abstract: Retro-inverso transformation has commonly been employed as a strategy both for the synthesis of proteolytically stable peptide analogues and for the detailed investigation of structure activity relationships. Herein, we adopted a similar strategy to probe the structure activity relationships of two biologically active tetradecapeptides. Analogues of the α-helical mastoparan, and the highly potent apoptogenic analogue mitoparan, were synthesized using d-amino acids assembled in both endogenous (inverso) and reverse (retro-inverso) orientations. For a more comprehensive comparison, our studies also included the retro l-enantiomer of both peptides. Contrary to expectation, comparative investigations of cytotoxicity, mast cell degranulation, and cellular penetration demonstrated that, while retro-inverso transformation abrogated the associated biological activities of these helical peptides, inverso homologues retained their bioactivities. Moreover, inverso mastoparan demonstrated the highest translocation efficacy of all analogues with much improved uptake kinetics compared to other cell penetrating peptides (CPPs) including the commonly employed inert vectors penetratin and tat. Data presented herein thus propound the utility of inverso mastoparan as a highly efficient peptide vector. Furthermore, correlation analysis of plasma membrane translocation and intracellular uptake efficacy further supports a two-compartment model of CPP import whereby the intracellular accumulation of polycationic peptides is dependent upon both the efficiency of transport into the cell and their subsequent accretion at distinct subcellular loci.
authors.affiliation: Research Institute in Healthcare Science, School of Applied Sciences, University of Wolverhampton, Wulfruna Street, Wolverhampton, United Kingdom. S.Jones4@wlv.ac.uk
authors.forename: Sarah
authors.initials: S
authors.lastname: Jones
authors.forename: John
authors.initials: J
authors.lastname: Howl
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014862:Wasp Venoms / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D014862:Wasp Venoms; C529760:mitoparan; C037500:mastoparan