Forskningsprojekt

1)      Utveckling av cellulära transportörer

Cellpenetrerande peptider, CPP, har en funktion som cellulära transportörer över biologiska membran. Då dessa CPP, eller transportaner, även kan bära med sig andra ämnen, såsom ett protein, så kan de bidra till nya metoder för forskning och terapeutiska applikationer. Mekanismerna bakom denna cellulära leverans är fortfarande oklar och är värd att studera i detalj. Utöver detta ligger vårt intresse i nuläget också i möjligheten att transportera läkemedel över blod-hjärn-barriären. Cellulär leverans av peptider, korta oligonukleotider såsom siRNA, peptide nukleinsyra oligomerer, proteiner och även transfektionsplasmider har möjliggjorts med CPP.

 

2)      Studier och mimik av protein-proteininteraktioner

Under de senaste åren, har protein-proteininteraktioner för utveckling av potentiella läkemedel väckt stort intresse från vår sida. Vi har koncentrerat oss på förståelsen av dessa interaktioner på 7TM receptornivå – G-proteiner och transkriptionsfaktorer i de fall signaltransduktionen tycks vara av avgörande betydelse.
De sjukdomar som är länkade till cellulära signaltransduktionssystem, som är intressanta för oss, är diabetes (NIDDM), Alzheimer’s sjukdom och cancer. Leveransen av dessa läkemedel över blod-hjärn-barriären och läkemedel med selektiv målsökning är också av intresse genom användandet av transportpeptiderna. Även här är de första resultaten mycket lovande och vi fortsätter med dessa studier.
 

Utvalda publikationer

1. Langel,Ü. (2015) Preface. Methods in Molecular Biology, 1324, v-viii.

2. Pooga,M., and Langel,Ü. (2015) Classes of cell-penetrating peptides. Methods in Molecular Biology, 1324, 3-28.

3. Uusna,J., Langel,K., and Langel,Ü. (2015) Toxicity, immunogenicity, uptake and kinetics methods for CPPs. Methods in Molecular Biology, 1324,133-148.

4. Helmfors,H., Lindberg,S., and and Langel,Ü. (2015) SCARA involvement in the uptake of nanoparticles formed by cell penetrating peptides. Methods in Molecular Biology, 1324, 163-174.

5. Pärn,K., Eriste,E. and Langel,Ü. (2015) The antimicrobial and antiviral applications of cell-penetrating peptides. Methods in Molecular Biology, 1324, 223-45.

6. Arukuusk,P., Pärnaste,L., Hällbrink,M., and Langel,Ü. (2015)  PepFects and NickFects  for the intracellular delivery of nucleic acids. Methods in Molecular Biology, 1324, 303-315.

7. Kurrikoff,K., Veiman,K.-L., and Langel,Ü. (2015)  CPP-based delivery system for in vivo gene delivery. Methods in Molecular Biology, 1324, 339-347.

8. Srimanee,A., Regberg,J., and Langel,Ü. (2015)  Application of CPPs for brain delivery. Methods in Molecular Biology, 1324, 349-356

9. Cerrato,C.P., Veiman,K.-L., and Langel,Ü. (2015) Advances in peptide delivery. Future Science, doi:10.4155/fseb2013.14.23.

10. Cerrato,C.P., Pirisinu,M., Vlahos,E.-N., and Langel,Ü. (2015) Novel cell-penetrating peptide targeting mitochondria. FASEB J., 29(11), 4589-4599.

11. Eriksson,J., Helmfors,H, and Langel,Ü. (2015) A high-throughput kinetic assay for RNA-cleaving deoxyribozymes. PLoS One, 10(8):e0135984.

12. Freimann,K., Kurrikoff,K., and Langel,Ü. (2015) Galanin receptors as a  potential target for neurological disease, Expert Opinion on Therapeutic Targets, 19(12), 1665-1676.

13. Guipponi,M., Chentouf,A., Webling,K.E.B., Freimann,K., Crespel,A., Nobile,C., Lemke,J.R., Hansen,J., Dorn,T., Lesca,G., Ryvlin,P., Hirsch,E., Rudolf,G., Rosenberg,D.S., Weber,Y., Becker,F., Helbig,I., Muhle,H., Salzmann,A., Chaouch,M., Oubaiche,M.L., Ziglio,S., Gehrig,C., Santoni,F., Pizzato,M., Langel,Ü., Antonarakis,S.E. (2015) Galanin pathogenic mutations in temporal lobe epilepsy. Human Molecular Genetics, 24(11), 3082-3091.

14. Helmfors,H., Eriksson,J., and Langel,Ü. (2015) Optimised luciferase assay for cell-penetrating peptide-mediated delivery of short oligonucleotides. Analytical Biochemistry, 484, 136-142.

15. Juks,K., Padari,K., Margus,H., Kriiska,A., Etverk,I., Arukuusk,P., Koppel,K., Ezzat,K., Langel,Ü., and Pooga,M. (2015) The role of endocytosis in the uptake and intracellular trafficking of PepFect14—nucleic acid nanocomplexes via class A scavenger receptors. Biochim.Biophys.Acta-Biomembranes,1848(12), 3205-3216

16. Järver,P., Zaghloul,E.M., Arzumanov,A.A., Saleh,A., McClorey,G., Hammond,S.M., Hällbrink,M., Langel,Ü., Smith, C.I.E., Wood,M.J.A., Gait,M.J., EL Andaloussi,S. (2015) Peptide nanoparticle delivery of charge-neutral splice switching morpholino oligonucleotides. Nucleic Acid Ther. 25(2), 65-77.

17. Lindberg,S., Regberg,J., Eriksson,J., Helmfors,H., Muñoz-Alarcón,A., Srimanee,A., Figueroa,R., Hallberg,E., Ezzat,K., and Langel,Ü. (2015) A convergent uptake route for peptide- and polymer-based nucleotide delivery systems. J.Control.Release, 206, 58-66.

18. Muñoz-Alarcón,A., Eriksson,J., and Langel,Ü. (2015) Novel efficient cell-penetrating peptide-mediated strategy for enhancing telomerase inhibitor oligonucleotides. Nucleic Acid Therapeutics. 25(6), 306-310.

19. Tudoran,O.M., Soritau,O., Balacescu,L., Pop,L., Meurice,G., Visan,S., Lindberg,S., Eniu,A., Langel,Ü., Balacescu,O., Berindan-Neagoe,I. (2015)  PDGF beta targeting in cervical cancer cells suggest a fine-tuning of compensatory signaling pathways to sustain tumorigenic stimulation. J.Cell.Mol.Med., 19(2), 371-382.

20. Veiman,K.-L., Künnapuu,K., Lehto,T., Kiisholts,K., Pärn,K., Langel,Ü., and Kurrikoff,K. (2015) PEG shielded MMP sensitive CPPs for efficient and tumor specific gene delivery in vivo. J.Control.Release, 209, 238-247.

21. Cerrato,C.P., Künnapuu,K., and Langel,Ü., (2016) CPPs with intracellular organelle targeting, Exp.Opinion Drug Del., 1-11.

22. Dash-Wagh,SW., Langel,Ü., and Ulfendahl,M. (2016) PepFect6 mediated siRNA delivery into organotypic cultures. Methods in Molecular Biology, 1364, 27-35.

23. Dowaidar,M., Regberg,J., Dobchev,D.A., Lehto,T., Hällbrink,M., Karelson,M., and Langel,Ü. (2016) QSAR refinement improves efficacy of generation of novel cell-penetrating peptides. Int.J.Pept.Res.Therap., doi:10.1007/s10989-016-9542-8.

24. Eriksson,J., and Langel,Ü. (2016) Quantitative microplate assay for real-time nuclease kinetics. PLOS One, 11(4), e0154099, DOI : 10.1371/journal.pone.0154099. 

25. Freimann,K., Arukuusk,P., Kurrikoff,K., Vasconcelos,L., Veiman,K.-L., Uusna,J., Margus,H., Garcia,A.T., Pooga,M., and Langel,Ü. (2016) Optimization of in vivo DNA delivery with NickFect peptide vectors. J.Control.Release, 241, 135-143.

26. Jevtuševskaja,J., Uusna,J., Andresen,L., Krõlov,K., Laanpere,M., Grellier,T., Tulp,I., and Langel,Ü., (2016) Combination with antimicrobial peptide lyses improves loop-mediated isothermal amplification based method for Chlamydia trachomatis detection directly in urine sample. BMC Infectious Diseases, 16 : 329, 1-8. doi: 10.1186/s12879-016-1674-0

27. Jones,S., Uusna,J., Langel,Ü., and Howl,J. (2016) Intracellular target-specific accretion of cell penetrating peptides and bioportides: Ultrastructural and biological correlates. Bioconj.Chem., 27(1), 121-129.

28. Kurrikoff,K., Gestin,M., and Langel,Ü. (2016) Recent in vivo advances in cell-penetrating peptide-assisted drug delivery. Expert Opinion on Drug Delivery, 13(3), 373-387.

29. Margus,H., Arukuusk,P., Langel,Ü., and Pooga,M. (2016) Characteristics of Cell-Penetrating Peptide/Nucleic Acid Nanoparticles, Molecular Pharmaceutics, 13, 172-179. 

30. Pae,J., Liivamägi,L., Lubenets,D., Arukuusk,P., Langel,Ü., and Pooga,M. (2016) Glycosaminoglycans are required for translocation of amphipathic cell-penetrating peptides across membranes. BBA-Biomembranes, 1858(8), 1860-1867.

31. Pärnaste,L., Arukuusk,P., Zagato,E., Braeckmans,K., and Langel,Ü. (2016) Methods to follow intracellular trafficking of cell-penetrating peptides. J. Drug Targeting, 24(6), 508-519.

32. Radwani,H., Lopez-Gonzales,M.J., Cattaert,D., Roca-Lapirot,O., Dobremez,E., Eiriksdottir,E., Langel,Ü., Favereaux,A., Errami,M, Landry,M., and Fossat,P. (2016) Cav1.2 and Cav1.3 l-type calcium channels independently control short- and long-term sensitization to pain. J.Physiol., doi: 10.1113/JP272725

33. Regberg,J., Vasconselos,L., Madani,F., Langel,Ü., and Hällbrink,M. (2016) pH-responsive PepFect cell-penetrating peptides. J.Pharmac., 501, 32-38.

34. Srimanee,A., Regberg,J., Hällbrink,M., Vajragupta,O., and Langel,Ü. (2016) Role of scavenger receptors in peptide-based delivery of plasmid DNA across a blood -brain barrier model. Int.J.Pharm., 500(1-2), 128-135.

35. Urgard,E., Lorents,A., Klaas,M., Padari,K., Viil,J., Runnel,T., Langel,K., Kingo,K., Tkaczyk,E., Langel,Ü., Maimets,T., Jaks,V., Pooga,M., Rebane,A. (2016) Pre-administration of PepFect6-microRNA-146a nanocomplexes inhibits inflammatory responses in keratinocytes and in a mouse model of irritant contact dermatitis. J.Control.Release, 235, 195-204.

36. Webling,K., Groves-Chapman,J., Runesson,J., Saar,I., Lang,A., Sillard,R., Jakovenko,E., Kofler,B., Holmes,P.V., and Langel,Ü. (2016) Pharmacological stimulation of GAL1R but not GAL2R attenuates kainic acid-induced neuronal cell death in the rat hippocampus. Neuropeptides, 58, 83-92.

37. Webling,K., Runesson,J., Lang,A., Saar,I., Kofler,B., and Langel,Ü. (2016) Ala5-galanin(2-11) is a GAL2  specific galanin analogue. Neuropeptides. In press. doi: 10.1016/j.npep.2016.08.008

38. Zhang,Z., Fang,P., He,B., Guo,L., Runesson,J., Langel,Ü.. Shi.,M., Zhu,Y., Bo,P. (2016) Central administration of galanin receptor 1 agonist M617 boosted insulin sensitivity in adipose cells of diabetic rats. J.Diabetes Res. 2016:9095648. doi: 10.1155/2016/9095648

 

Böcker

Ü. Langel, B. Cravatt, A. Gräslund, G. von Heijne, T.Land, S.Niessen, and M.Zorko (2010) Introduction to peptides and proteins, CRC Press, Taylor and Francis Group, Boca Raton, London, New York, ISBN : 978-1-4200-6412-4.
 
Langel, Ü., Ed. (2011) Cell-Penetrating Peptides. Methods and Protocols. Methods in Molecular Biology, Humana Press., vol. 683, ISBN: 978-1-60761-918-5.