Malgorzata Honcharenko (Wenska)
Developing methods for delivery of Oligonucleotide conjugates as therapeutics at Karolinska Institutet
Developing new methods for improving action of therapeutic modalities like oligonucleotides, peptides and bioconjugates is a fundament of my research at KI. I examine a range of scientific tools with the aim to improve targeting therapeutics to precise destination in the body, contributing to the discoveries of the future precise therapies. Many therapeutic approaches can be improved and unwanted side effects avoided. We should design therapeutics in such a way that they will be delivered and released precisely to the affected organ/tissue in the body (targeted delivery approach).
As a part of European network I am applying developed at KI methods for improvements of oligonucleotide based therapies (e.g. COST Action: Delivery of Antisense RNA Therapeutics). As a bioconjugation chemist I seek interdisciplinary collaborations with medicinal, biological and biochemical experts to explore the potential of the methods I developed to improve therapies. Some of the key collaborators include: Prof. Aartsma-Rus at the Leiden University Medical Center (LUMC), The Netherlands, and Shalini Andersson Chief Scientist New Therapeutic Modalities at AstraZeneca, Gothenburg.
After working on several projects developing more effective therapeutics I recognize the importance of finding solution to the general problem of their precise delivery. Methods that I developed at KI allows for efficient conjugation of receptor specific entities to oligonucleotides. That improves delivery of those molecules to the place of action. However, ligand-receptor interaction is usually weak, and current methods allow for conjugations of just several such ligands to oligonucleotide. On the other hand, exosomes that are 30-200 nm in diameter, can be equipped with several hundreds of copies (~ 600, depending of the EVs size) magnifying the targeting effect. This is the reason why bio-engineered EVs may be just the answer that scientists are looking for in targeted drug delivery and a main collaborative project at the moment.
15 Selected Publications
(1) Smith, E., Moreno, P., Stroemberg, R., and Wenska, M. (2015). Patent, US 9067964 B2 20150630
(2) Honcharenko, M., Honcharenko, D., and Strömberg, R. (2019) Attachment of Peptides to Oligonucleotides on Solid Support Using Copper(I)-Catalyzed Huisgen 1,3-Dipolar Cycloaddition. Oligonucleotide-Based Therapies: Methods and Protocols, Methods in Molecular Biology vol. 2036.
(3) Honcharenko, M., Honcharenko, D., and Stroemberg, R. (2019) Efficient Conjugation to Phosphorothioate Oligonucleotides by Cu-Catalyzed Huisgen 1,3-Dipolar Cycloaddition. Bioconjugate Chem. 30, 1622-1628.
(4) Gissberg, O. I., Jezowska, M., Zaghloul, E. M., Bungsu, N. I., Stroemberg, R., Smith, C. I. E., Lundin, K. E., and Honcharenko, M. (2016) Fast and efficient synthesis of Zorro-LNA type 3'-5'-5'-3' oligonucleotide conjugates via parallel in situ stepwise conjugation. Org. Biomol. Chem. 14, 3584-3590.
(5) Honcharenko, M., Bestas, B., Jezowska, M., Wojtczak, B. A., Moreno, P. M. D., Romanowska, J., Baechle, S. M., Darzynkiewicz, E., Jemielity, J., Smith, C. I. E., and Stroemberg, R. (2016) Synthetic m3G-CAP attachment necessitates a minimum trinucleotide constituent to be recognised as a nuclear import signal. RSC Adv. 6, 51367-51373.
(6) Jezowska, M., Honcharenko, D., Ghidini, A., Stroemberg, R., and Honcharenko, M. (2016) Enabling Multiple Conjugation to Oligonucleotides Using "Click Cycles". Bioconjugate Chem. 27, 2620-2628.
(7) Wojtczak, B. A., Warminski, M., Kowalska, J., Lukaszewicz, M., Honcharenko, M., Smith, C. I. E., Stromberg, R., Darzynkiewicz, E., and Jemielity, J. (2016) Clickable trimethylguanosine cap analogs modified within the triphosphate bridge: synthesis, conjugation to RNA and susceptibility to degradation. RSC Adv. 6, 8317-8328.
(8) Ruiz Garcia, Y., Iyer, A., Van Lysebetten, D., Vladimir Pabon, Y., Louage, B., Honcharenko, M., De Geest, B. G., Edvard Smith, C. I., Stromberg, R., and Madder, A. (2015) Sequence-selective DNA recognition and enhanced cellular up-take by peptide-steroid conjugates. Chem. Commun. (Cambridge, U. K.) 51, 17552-17555.
(9) Honcharenko, M., Zytek, M., Bestas, B., Moreno, P., Jemielity, J., Darzynkiewicz, E., Smith, C. I. E., and Stroemberg, R. (2013) Synthesis and evaluation of stability of m3G-CAP analogues in serum-supplemented medium and cytosolic extract. Bioorg. Med. Chem. 21, 7921-7928.
(10) Honcharenko, M., Romanowska, J., Alvira, M., Jezowska, M., Kjellgren, M., Edvard Smith, C. I., and Stroemberg, R. (2012) Capping of oligonucleotides with "clickable" m3G-CAPs. RSC Adv. 2, 12949-12962.
(11) Jezowska, M., Romanowska, J., Bestas, B., Tedebark, U., and Honcharenko, M. (2012) Synthesis of biotin linkers with the activated triple bond donor [p-(N-propynoylamino)toluic acid] (PATA) for efficient biotinylation of peptides and oligonucleotides. Molecules 17, 14174-14185.
(12) Wenska, M., Alvira, M., Steunenberg, P., Stenberg, A., Murtola, M., and Stroemberg, R. (2011) An activated triple bond linker enables "click" attachment of peptides to oligonucleotides on solid support. Nucleic Acids Res. 39, 9047-9059.
(13) Murtola, M., Wenska, M., and Stroemberg, R. (2010) PNAzymes That Are Artificial RNA Restriction Enzymes. J. Am. Chem. Soc. 132, 8984-8990.
(14) Bramsen, J. B., Laursen, M. B., Nielsen, A. F., Hansen, T. B., Bus, C., Langkjaer, N., Babu, B. R., Hojland, T., Abramov, M., Van Aerschot, A., Odadzic, D., Smicius, R., Haas, J., Andree, C., Barman, J., Wenska, M., Srivastava, P., Zhou, C., Honcharenko, D., Hess, S., Mueller, E., Bobkov, G. V., Mikhailov, S. N., Fava, E., Meyer, T. F., Chattopadhyaya, J., Zerial, M., Engels, J. W., Herdewijn, P., Wengel, J., and Kjems, J. (2009) A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity. Nucleic Acids Res. 37, 2867-2881.
(15) Moreno, P. M. D., Wenska, M., Lundin, K. E., Wrange, O., Stroemberg, R., and Smith, C. I. E. (2009) A synthetic snRNA m3G-CAP enhances nuclear delivery of exogenous proteins and nucleic acids. Nucleic Acids Res. 37, 1925-1935.