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PolExGene meeting May, 22-23 2008 Prague

PolExGene meeting May, 22-23 2008 Prague. CNRS Montpellier (France), Partner 10 Max Mousseron Institute of Biomolecules Pr. Jean Martinez Dr. Muriel Amblard Dr. Gilles Subra Thomas Raimondi Luc Brunel. WP 2 : Synthesis of Selected CPP. WP 3 : Synthesis of Selected CIP.

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PolExGene meeting May, 22-23 2008 Prague

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  1. PolExGene meeting May, 22-23 2008 Prague CNRS Montpellier (France), Partner 10 Max Mousseron Institute of Biomolecules Pr. Jean Martinez Dr. Muriel Amblard Dr. Gilles Subra Thomas Raimondi Luc Brunel WP 2 : Synthesis of Selected CPP WP 3 : Synthesis of Selected CIP

  2. Objectives of our group Selection and synthesis of Cell Penetrating Peptides (CPP) • Peptides deriving from protein transduction domain (Penetratin, TAT) • Polyarginine-based peptides CPP-containing polyplexes (covalent anchoring) CPP + polyplexes (mixtures) Selection and synthesis of Cell Interacting Peptides (CIP) • RGD-based peptides Increase membrane-cell interaction

  3. Cell Penetrating Peptide Synthesis Peptides from protein transduction domain (Penetratin, TAT) delivered before midterm Partn n° Penetratin 1, 5, 3 Penetratin H-RQIKIWFQNRRMKWKK-OH JMV3485 JMV3572 Acetyl-Penetratin Ac-RQIKIWFQNRRMKWKK-OH 1, 5 JMV3510 Ac-Cys-RQIKIWFQNRRMKWKK-OH 1, 5 AcCys-penetratin-OH JMV3581 Penetratin-NH2 H-RQIKIWFQNRRMKWKK-NH2 5 JMV3582 Acetyl-Penetratin-NH2 Ac-RQIKIWFQNRRMKWKK-NH2 5 RhodB-RQIKIWFQNRRMKWKK-OH JMV3647 RhodB-Penetratin 3 Tat JMV3535 5 Tat-NH2 H-GRKKRRQRRRPPQ-NH2 JMV3536 5 Acetyl-Tat-NH2 Ac-GRKKRRQRRRPPQ-NH2 JMV3484 Acetyl-Tat(48-57)-NH2 5 Ac-GRKKRRQRRR-NH2 JMV3481 5 Tat(48-57) H-GRKKRRQRRR-OH JMV3508 5 Tat(Arg3,4) H-GRRRRRQRRRPPQ-OH JMV3509 Acetyl-Tat(Arg3,4) 5 Ac-GRRRRRQRRRPPQ-OH

  4. Cell Penetrating Peptide Synthesis Polyarginine-based peptides delivered before midterm Partn n° Ac-(Arg)8-OH Ac-RRRRRRRR-OH JMV3482 5 Ac-(Arg)11-OH Ac-RRRRRRRRRRR-OH JMV3483 5 H-(Arg)8-NH2 H-RRRRRRRR-NH2 JMV3506 5 Ac-(Arg)8-NH2 Ac-RRRRRRRR-NH2 JMV3507 5 Biotine-(Arg)8-NH2 Biotine-RRRRRRRR-NH2 JMV3674 8

  5. Polyarginine derived CPP Cys derivatives forCPP-containing polyplexes Ac-Cys-(Arg)8-NH2 Ac-Cys-RRRRRRRR-NH2 JMV3781 1 Cys-CPP spacer derivatives Ac-Cys--RRRRRRR-NH2 Spacer CPP anchoring Partn n° Ac-Cys-NH(CH2)3CO-(Arg)8-NH2 JMV3782 1 Ac-Cys-NH(CH2)5CO-(Arg)8-NH2 JMV3783 1 Ac-Cys-NH(CH2)7CO-(Arg)8-NH2 JMV3784 1 Ac-Cys-NH(CH2CH2O)2CH2CO-(Arg)8-NH2 JMV3785 1 Ac-Cys-PEG11-(Arg)8-NH2 JMV3801 1

  6. Polyarginine derived CPP FITC-CPP spacer derivatives : control of penetration into cells FITC--RRRRRRR-NH2 Spacer CPP Fluorescein moiety Partn n° FITC-NH(CH2)3CO-(Arg)8-NH2 JMV3887 5 FITC-NH(CH2)5CO-(Arg)8-NH2 JMV3888 5 FITC-NH(CH2)7CO-(Arg)8-NH2 JMV3889 5 FITC-NH(CH2CH2O)2CH2CO-(Arg)8-NH2 JMV3890 5 FITC-PEG11-(Arg)8-NH2 JMV3891 5

  7. Cell Interacting Peptide Synthesis RGD-based peptides (avb3 integrin) Partn n° H-Cys-Gly-Gly-Arg-Gly-Asp-Ser-OH JMV3622 1 cyclo[Arg-Gly-Asp-(D)Phe-Lysw](H-Cys-Gly-Gly-) JMV3619 1

  8. CPP Synthesis: in progress Cys-CPP spacer derivatives R--RRRRRRR-NH2 CPP Rigid Spacer R = Ac-Cys or FITC R-b-Ala-(Pro-Gly)3-(Arg)8-NH-Resin (Rink amide) Clivage, purification Partn n° 1, 5 R-b-Ala-(Pro-Gly)3-(Arg)8-NH2 (Pro-Gly)3 : helical structure with an average distance of 7 Å Bioconjugate Chem. 2007, 1101.

  9. Progress and Perspectives New CPP :D-Arg or b-h-Arg oligomers as CPP Rink amide resin X-(D-Arg)8-NH2 X-(b-homoArg)8-NH2 X will depend on the results of the other series New CIP Selection of selective targets?

  10. Perspectives «PEG-Detachable Polyplex Micelles Based on Disulfide-Linked Block Catiomers as Bioresponsive Nonviral Gene Vectors », JACS 2008, 6001. To prevent non-specific trapping and to reduce toxicity, PEI polymers have been grafted with polyethylene glycol (PEG), a hydrophilic polymer, which shields the positive surface charge but maintains the solubility of the particles. PEGylation has been shown to prevent erythrocyte aggregation, reduce cytotoxicity and significantly prolong circulation time

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