Unit for Organic and Bioorganic Chemistry
The current research is largely focused on nucleic acids and peptides for potential use in therapy. We are working with novel concepts in pharmaceutical development, i.e. “new modalities” as they are known, especially development of methodology that enables synthesis of these classes of molecules.
This also involves synthesis of biomolecules with new modifications that provide beneficial properties and oligonucleotide and peptide conjugates that equip the molecules with entities that enhance catalysis, delivery and/or targeting. Over the past ten years we have become more and more involved in translational research where new concepts show promise towards being moved further towards the clinic.
Stabilised, Cell Penetrating and Target Seeking Oligonucleotides for Enhanced Therapy
Oligonucleotide (ON) therapy is limited by inefficient in vivo delivery. To address this, we are developing methods for conjugation to enable constructs of oligonucleotide equipped with different entities, including multiple conjugation of different classes of molecules to ONs. We are developing “cell penetration oligonucleotides”, in order to address both cellular uptake and reduction of phosphorothioate modifications. We are looking at ON conjugates with entities for the targeting of specific tissues, e.g. heart and muscle cells where we collaborate with academic and industrial partners on antisense and splice switching ON therapy
Oligonucleotide Based Artificial Nucleases and PNAzymes
A special part of modified ONs for potential therapeutic use is oligonucleotide-based artificial nucleases (OBANs). We have developed these to the state of being potentially useful tools, e.g. as artificial RNA restriction enzymes. We aim to make these biocompatible and efficient enough for use in a cellular environment and to explore potential for disease therapy. Recent peptide nucleic acid (PNA) based zinc ion dependent nucleases (PNAzymes) are highly efficient for cleavage of RNA and once crystal structures with substrate analogues are obtained, further development will follow.
Treatment of infections by means of substances that induce our own defense against microbes and Aβ-peptide ligands for potential treatment of Alzheimer’s Disease (AD)
Over the past years we have developed substances for the treatment of infections through induction of body-own antimicrobial peptides. Potent inducers of antimicrobial peptides are currently being looked at for further development within a company. Ligands that stabilise the Aβ peptide and prevent toxicity of Aβ aggregates may hold promise for treatment of AD and this is now also in the hands of a pharmaceutical company.
(roughly ordered by interconnection):
Amyloid-β Peptide Targeting Peptidomimetics for Prevention of Neurotoxicity.
Honcharenko D, Juneja A, Roshan F, Maity J, Galán-Acosta L, Biverstål H, et al
ACS Chem Neurosci 2019 03;10(3):1462-1477
Further Probing of Cu2+-Dependent PNAzymes Acting as Artificial RNA Restriction Enzymes.
Luige O, Murtola M, Ghidini A, Strömberg R
Molecules 2019 Feb;24(4):
Efficient Conjugation to Phosphorothioate Oligonucleotides by Cu-Catalyzed Huisgen 1,3-Dipolar Cycloaddition.
Honcharenko M, Honcharenko D, Strömberg R
Bioconjug. Chem. 2019 06;30(6):1622-1628
Potent Inducers of Endogenous Antimicrobial Peptides for Host Directed Therapy of Infections.
Ottosson H, Nylén F, Sarker P, Miraglia E, Bergman P, Gudmundsson GH, et al
Sci Rep 2016 11;6():36692
Milton S Honcharenko D Moreno P Rocha C Smith E, Strömberg R (2015) Nuclease resistant oligonucleotides with cell-penetrating properties Chem Comm 51, 4044; Milton S, Ander C, Honcharenko M, Honcharenko D, Yeheskiely E, Strömberg R (2013) Synthesis and stability of a 2’-O-(N-(aminoethyl)carbamoyl)-methyladenosine containing dinucleotide Eur J Org Chem 7184; Milton S Ander C Yeheskiely E Strömberg R (2012) Stability of a 2’-O-(carbamoylmethyl) adenosine containing dinucleotide Eur J Org Chem 539.
Jezowska M, Honcharenko D; Ghidini A; Strömberg R; Honcharenko M. (2016) Enabling Multiple Conjugation to Oligonucleotides Using “Click Cycles”. Bioconjugate Chem., 27, 2620; Wenska M, Alvira M, Steunenberg, P, Stenberg Å, Murtola, M and Strömberg R (2011) An Activated Triple Bond Linker Enables “Click” Attachment of Peptides to Oligonucleotides Nucl Acids Res., 39, 9047; Zaramella S, Yeheskiely E, Strömberg R (2004) A Method for Solid Phase Synthesis of Oligonucleotide 5’-Peptide Conjugates Using Acid Labile a-Amino Protection J Am Chem Soc, 126, 14029.
Ghidini A, Murtola M, Strömberg, R (2016) Influence of conjugation and other structural changes on the activity of Cu2+ based PNAzymes. Org Biomol Chem, 14, 2768; Ghidini A, Murtola M, Strömberg R. (2015) Oligonucleotide based artificial ribonucleases DNA in Supramolecular Chemistry and Nanotechnology, Wiley, Chapter 3.2; Murtola M, Wenska M, Strömberg R (2010) PNAzymes that are artificial RNA restriction enzymes J Am Chem Soc, 132, 8984; Murtola M, Strömberg R (2008) PNA Based Artificial Nucleases Displaying Catalysis with Turnover in Cleavage of a Leukemia related RNA model Org Biomol Chem 6, 3837; Åström H, Williams NH, Strömberg R (2003) Oligonucleotide based artificial nuclease (OBAN) systems. Bulge size dependence and positioning of catalytic group in cleavage of RNA bulges. Org Biomol Chem 1461
Honcharenko M; Bestas B; Jezowska M; Wojtczak BA; Moreno PMD; Romanowska J; Bächle SM; Darzynkiewicz E; Jemielity J; Smith CIE; Strömberg R. (2016) Synthetic m3G-CAP attachment necessitates a minimum trinucleotide constituent to be recognised as a Nuclear Import Signal. RSC Advances, 6, 51367; Honcharenko M; Romanowska J; Alvira M; Jezowska M; Kjellgren M; Smith CIE; Strömberg R (2012) Capping of oligonucleotides with "clickable" m3G-CAPs RSC Advances, 2, 12949; Moreno P, Wenska M, Lundin K, Wrange Ö, Strömberg R, Smith E (2009) A synthetic snRNA m3G-CAP enhances nuclear delivery of exogenous proteins and nucleic acids. Nucl. Acids Res, 37, 1925.
Ottosson H; Nylen F; Sarker P; Miraglia E; Bergman P; Gudmundsson GH; Raquib R; Agerberth B; Strömberg R. (2016) Potent Inducers of Endogenous Antimicrobial Peptides for host Directed Therapy of Infections. Sci Rep. 6:36692. DOI: 10.1038/srep36692.
Ghidini A; Bergquist H; Punga T; Zain R; Strömberg R. (2016) Clamping of RNA with PNA enables targeting of microRNA. Org Biomol Chem 14, 5210;
Ghidini A Ander C Winqvist A Strömberg R (2013) An RNA modification with remarkable resistance to RNase A. Chem Comm 49, 9036; Winqvist A Strömberg R. (2008) Nucleoside 3’-Deoxy-3’-C-Methylenephosphinates Part 3. An investigation on Condensing Agents for Phosphinate Ester Formation with Nucleoside 5’-Hydroxyl Functions. Eur J Org Chem, 1705; Winqvist A Strömberg R (2002) Reactions of 3’-C-Halomethyl and 3’-C-Sulfonylmethyl Uridines with Phosphinic Acid Derivatives. Synthesis of Building Blocks for Oligonucleotides Containing 3’-C-Methylenephosphonate Linkages Eur J Org Chem, 1509; Winqvist A, Strömberg R (2001) Stereoselectivity in the synthesis of 3'-deoxy-3'-C-(hydroxymethyl) uridines by hydroboration and conversion into a building block for various 3'-deoxy-3'-C-(methylene)uridine analogues Eur J Org Chem, 4305.
Maity J, Honcharenko D, Strömberg R. (2015) Synthesis of Triamino Acid Building Blocks with Different Lipophilicities. PLoS One, 10, e0124046; Honcharenko D; Bose PP; Maity J; Kurudenkandy FR; Juneja A; Flöistrup E; Henrik Biverstål H; Johansson J; Nilsson L; Fisahn A; Strömberg R. (2014) Synthesis and Evaluation of Antineurotoxicity Properties of an Amyloid-β Peptide Targeting Ligand Containing a Triamino Acid. Org. Biomol. Chem., 12, 6684-6693; Nerelius, C.; Sandegren, A.; Sargsyan, H.; Raunak, R.; Leijonmarck, H.; Chatterjee, U.; Fisahn, A.; Imarisio, S.; Lomas, D. A.; Crowther, D. C.; Strömberg, R.; Johansson, J. (2009) α-Helix targeting reduces amyloid-β peptide toxicity. Proc. Natl. Acad. Sci. USA, 106, 9191.
Murtola M, Zaramella S, Yeheskiely E, Strömberg R (2010) Cationic Peptides that Increase the Thermal Stability of 2’-O-MeRNA/RNA Duplexes, but that do not Affect DNA/DNA Melting ChemBioChem, 11, 2606; Sandbrink J, Ossipov D, Åström H, Strömberg R (2005), Investigation of Potential RNA-bulge Stabilising Elements, J Mol Recognition, 18, 318; Madder A, Ehrl R, Stromberg, R. (2003) Stabilisation of RNA Bulges by Oligonucleotide Complements Containing an Adenosine Analogue. ChemBioChem, 4, 1194.
Rozners E Katkevica D Strömberg R (2007) Oligoribonucleotide analogues containing a mixed backbone of phosphodiester and formacetal internucleoside linkages, together with vicinal 2'-O-methyl groups ChemBioChem 8, 537; Rozners, E., Katkevica, D., Bizdena, E. and Strömberg, R. (2003) Synthesis and Properties of RNA Analogues Having Amides as Interuridine Linkages at Selected Positions, J Am Chem Soc 125, 12125; Rozners E. Strömberg, R. (1997) Synthesis and properties of oligoribonucleotides having formacetal internucleoside linkages J Org Chem, 62, 1846.
Åström, H., Limen, E. and Strömberg, R. (2004) The Acidity of Secondary Hydroxyls in ATP and Adenosine Analogues, and the question of a 2’,3’ hydrogen bond in ribonucleosides, J Am Chem Soc 126, 14710; Sjögren, A-S., Pettersson, E., Sjöberg, B-M. & Strömberg, R. (1997) Metal ion interaction with cosubstrate in self-splicing of group I introns. Nucl Acids Res, 25, 648;
Almer, H., Stawinski, J. & Strömberg, R. (1996) Solid support synthesis of all-Rp-oligo(ribonucleoside phosphorothioate)s, Nucleic Acids Res., 24, 3811. Almer, H. & Strömberg, R. (1996) Base-catalysis and leaving group dependence in intramolecular alcoholysis of uridine 3'-(aryl phosphorothioate)s. J. Am. Chem. Soc., 118, 7921; Oivanen, M., Almer, H., Strömberg, R. & Lönnberg, H. (1995), Hydrolytic reactions of the diastereomeric phosphoromonothioate analogs of uridylyl(3',5')uridine: Kinetics and mechanisms for desulfurization, phosphoester hydrolysis and transesterification to the 2',5'-isomers. J. Org. Chem., 60, 5620.
Stawinski J, Strömberg R (2005) Di and Oligonucleotide Synthesis Using H-Phosphonate Chemistry. In Oligonucleotide synthesis: Methods and applications; Edited by Piet Herdewijn; Humana Press, Totowa New Jersey, 81; Sigurdsson S, Strömberg R. (2002) The H-Phosphonate Approach to Oligonucleotide Synthesis. An Investigation on the Mechanism of the Coupling Step. J. Chem Soc. Perkin Trans 2, 1682; Garegg PJ, Henrichson C, Lindh, I, Regberg T, Stawinski J, Strömberg R (1986) Nucleoside H-phosphonates. III. Chemical synthesis of oligodeoxy-ribonucleotides by the hydrogenphosphonate approach. Tetrahedron Lett. 27, 4051; Garegg PJ, Henrichson C, Lindh I, Regberg T, Stawinski J, Strömberg, R (1986) Nucleoside H-phosphonates IV. Automated solid phase synthesis of oligo-ribonucleotides by the hydrogenphosphonate approach. Tetrahedron Lett. 27, 4055; Garegg PJ, Regberg T, Stawinski J, Strömberg R (1986) Nucleoside hydrogenphosphonates in oligonucleotide synthesis Chemica Scripta 26, 59.; Garegg PJ, Regberg T, Stawinski J, Strömberg R. (1985) Formation of internucleotidic bonds via phosphonate intermediates Chemica Scripta 25, 280.
Westman E, Strömberg R. (1994) Removal of t-butyldimethylsilyl protection in RNA-synthesis. Triethylamine trihydrofluoride (TEAx3HF) is a more reliable alternative to tetrabutylammonium fluoride (TBAF). Nucl Acids Res, 22 , 2430; Rozners E, Westman E, Strömberg R. (1994) Evaluation of 2'-hydroxyl protection in RNA-synthesis using the H-phosphonate approach. Nucl Acids Res, 22, 94; Stawinski J, Strömberg R, Thelin M, Westman E (1988) Studies on the t-butyl-dimethylsilyl group as 2´-O-protection in oligoribonucleotide synthesis via the H-phosphonate approach. Nucl Acids Res, 16, 9285.
Lönnberg H, Strömberg R, Williams A (2004) Compelling Evidence for a Stepwise Mechanism of the Alkaline Cyclisation of Uridine 3’-phosphate Esters Org Biomol Chem 2165: Mikkola S, Stenman E, Nurmi K, Yousefi-Salakdeh E, Strömberg R, Lönnberg H (1999) The mechanism of the metal ion promoted cleavage of RNA phosphodiester bonds involves a general acid catalysis by the metal aquo ion on the departure of the leaving group.” J Chem Soc Perkin Trans 2, 1619; Kosonen M, Yousefi-Salakdeh E, Strömberg R, Lönnberg H, (1998) pH- and Buffer-independent Cleavage and Mutual Isomerization of Uridine 2’ and 3’-alkylphosphodiesters: Implications for the Buffer Catalyzed Cleavage of RNA J Chem Soc Perkin Trans 2, 1589; Kosonen M, Yousefi-Salakdeh E, Strömberg R, Lönnberg H. Mutual Isomerization of Uridine 2’ and 3’-alkylphosphates and Cleavage of a 2’,3’-cyclic Phosphate: The Efffect of the alkyl Group on the Hydronium- and Hydroxide-ion-catalyzed Reactions. J. Chem. Soc. Perkin Trans 2, 1997, 2661
Chandler AJ, Hollfelder F, Kirby AJ, O`Carroll F, Strömberg R (1994) Models for enzyme catalysed phosphate transfer: Comparisons of reactivity towards neighbouring hydroxyl for phosphodiester anions and acids. General base catalysis of the cyclisation of a hydroxyalkyl phosphate triester. J Chem Soc Perkin Trans II 327; Camilleri P, Jones RFD, Kirby AJ, Strömberg R (1994) Nucleophilic catalysis of glycoside hydrolysis. The hydrolysis of 4-nitrophenyl a and b-D-glucopyranoside tetraphosphates. J Chem Soc Perkin Trans II 2085.