Mitoparans: mitochondriotoxic cell penetrating peptides and novel inducers of apoptosis.

2.50
Hdl Handle:
http://hdl.handle.net/2436/30467
Title:
Mitoparans: mitochondriotoxic cell penetrating peptides and novel inducers of apoptosis.
Authors:
Jones, Sarah; Martel, Cecile; Belzacq-Casagrande, Anne-Sophie; Brenner, Catherine; Howl, John D.
Abstract:
Introduction: The amphipathic helical peptide mastoparan (MP; H-INLKALAALAKKIL-NH2) inserts into biological membranes to modulate the activity of heterotrimeric G proteins and other targets. Moreover, whilst cell free models of apoptosis demonstrate MP to facilitate mitochondrial permeability transition and release of apoptogenic cytochrome c, MP-induced death of intact cells has been attributed to its non-specific membrane destabilising properties (necrotic mechanisms). However, MP and related peptides are known to activate other signalling systems, including p42/p44 MAP kinases and could therefore, also modulate cell fate and specific apoptotic events. The ability of MP to facilitate mitochondrial permeability in cell free systems has lead to proposals that MP could be of utility in tumour therapeutics provided that it conferred features of cellular penetration and mitochondrial localization. We have recently reported that our highly potent amphipathic MP analogue mitoparan (mitP; [Lys5,8Aib10]MP; Aib = -aminoisobutyric acid) specifically promotes apoptosis of human cancer cells, as was confirmed by in situ TUNEL staining and activation of caspase-3. Moreover, we have also demonstrated that mitP penetrates plasma membranes and redistributes to co-localize with mitochondria. Complementary studies, using isolated mitochondria, further demonstrated that mitP, through co-operation with a protein of the permeability transition pore complex voltage-dependent anion channel (VDAC), induced swelling and permeabilization of mitochondria, leading to the release of the apoptogenic factor cytochrome c. An expanding field of peptide and cell penetrating peptide (CPP) research has focussed on the selective targeting of tumours by engineering constructs that incorporate cell-specific or tissue–specific address motifs. Peptidyl address motifs could enhance the selectivity of drug delivery whilst the improved cellular uptake offered by CPP enhances bioavailability. Thus and as a potential therapeutic strategy, we extended our findings to design target-specific mitP analogues. The integrin-specific address motif RGD and a Fas ligand mimetic WEWT were incorporated by N-terminal acylation of mitP to produce novel tandem-linked chimeric peptides.
Citation:
In: Wilce, J. (Ed.), Proceedings of the 4th International Peptide Symposium, in conjunction with the 7th Australian Peptide Conference and the 2nd Asia-Pacific International Peptide Symposium, 21-25 October 2007, Cairns, Great Barrier Reef, Queensland, Australia.
Publisher:
Australian Peptide Association
Issue Date:
2007
URI:
http://hdl.handle.net/2436/30467
Additional Links:
http://www.peptideoz.org/proceedings.php
Type:
Meetings & Proceedings
Language:
en
Description:
Acknowledgments The authors would like to thank Keith Holding at the University of Wolverhampton for his outstanding technical support. This work was supported in part by Samantha Dickson Brain Tumour Trust.
Appears in Collections:
Molecular Pharmacology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorJones, Sarah-
dc.contributor.authorMartel, Cecile-
dc.contributor.authorBelzacq-Casagrande, Anne-Sophie-
dc.contributor.authorBrenner, Catherine-
dc.contributor.authorHowl, John D.-
dc.date.accessioned2008-06-25T16:12:31Z-
dc.date.available2008-06-25T16:12:31Z-
dc.date.issued2007-
dc.identifier.citationIn: Wilce, J. (Ed.), Proceedings of the 4th International Peptide Symposium, in conjunction with the 7th Australian Peptide Conference and the 2nd Asia-Pacific International Peptide Symposium, 21-25 October 2007, Cairns, Great Barrier Reef, Queensland, Australia.en
dc.identifier.urihttp://hdl.handle.net/2436/30467-
dc.descriptionAcknowledgments The authors would like to thank Keith Holding at the University of Wolverhampton for his outstanding technical support. This work was supported in part by Samantha Dickson Brain Tumour Trust.en
dc.description.abstractIntroduction: The amphipathic helical peptide mastoparan (MP; H-INLKALAALAKKIL-NH2) inserts into biological membranes to modulate the activity of heterotrimeric G proteins and other targets. Moreover, whilst cell free models of apoptosis demonstrate MP to facilitate mitochondrial permeability transition and release of apoptogenic cytochrome c, MP-induced death of intact cells has been attributed to its non-specific membrane destabilising properties (necrotic mechanisms). However, MP and related peptides are known to activate other signalling systems, including p42/p44 MAP kinases and could therefore, also modulate cell fate and specific apoptotic events. The ability of MP to facilitate mitochondrial permeability in cell free systems has lead to proposals that MP could be of utility in tumour therapeutics provided that it conferred features of cellular penetration and mitochondrial localization. We have recently reported that our highly potent amphipathic MP analogue mitoparan (mitP; [Lys5,8Aib10]MP; Aib = -aminoisobutyric acid) specifically promotes apoptosis of human cancer cells, as was confirmed by in situ TUNEL staining and activation of caspase-3. Moreover, we have also demonstrated that mitP penetrates plasma membranes and redistributes to co-localize with mitochondria. Complementary studies, using isolated mitochondria, further demonstrated that mitP, through co-operation with a protein of the permeability transition pore complex voltage-dependent anion channel (VDAC), induced swelling and permeabilization of mitochondria, leading to the release of the apoptogenic factor cytochrome c. An expanding field of peptide and cell penetrating peptide (CPP) research has focussed on the selective targeting of tumours by engineering constructs that incorporate cell-specific or tissue–specific address motifs. Peptidyl address motifs could enhance the selectivity of drug delivery whilst the improved cellular uptake offered by CPP enhances bioavailability. Thus and as a potential therapeutic strategy, we extended our findings to design target-specific mitP analogues. The integrin-specific address motif RGD and a Fas ligand mimetic WEWT were incorporated by N-terminal acylation of mitP to produce novel tandem-linked chimeric peptides.en
dc.language.isoenen
dc.publisherAustralian Peptide Associationen
dc.relation.urlhttp://www.peptideoz.org/proceedings.phpen
dc.subjectMolecular Biologyen
dc.subjectPeptidesen
dc.subjectCell Penetrating Peptides (CPP)en
dc.subjectCPPen
dc.subjectPeptide Mastoparanen
dc.subjectMastoparanen
dc.subjectMitoparansen
dc.subjectMitochondriaen
dc.subjectApoptosisen
dc.subjectCytotoxicityen
dc.titleMitoparans: mitochondriotoxic cell penetrating peptides and novel inducers of apoptosis.en
dc.typeMeetings & Proceedingsen
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