Structural features of nucleic acids and organic molecules as anti-sea drugs (2609)

The headline prof.dr.sc. Ivo Piantanida, zn. advisor-permanent choice

Ruđer Boskovic Institute

Understand the structural characteristics of nucleic acids and molecular recognition of nucleic acid units as the basis of the approach to finding antitumor drugs. Get to know the methods used to determine the interactions of small organic molecules with nucleic acids.

Basic structural features of DNA and RNA; covalent and non-covalent interactions in nucleic acids. Secondary structures of a higher order: triple and quadruple coils. X-ray structural analysis and computer models of nucleic acids. Molecular recognition of nucleic acid units – the basis of a rational approach to finding anticancer drugs. Recognition of special structural motifs of nucleic acids (hairpins, protrusions), recognition of single-stranded and two-stranded domains. Types of binding of organic molecules to nucleic acids, electrostatic interactions, binding in a small and large groove of the double coil, intercaling. Examples of molecules that bind into the grooves of a double coil (groove binders). Intercalators, examples of classical, nonclassical and bisintercalators. A brief overview of common experimental methods in the investigation of interactions of small organic molecules with synthetic and natural DNA and RNA polynucleotides: spectroscopic methods (UV, fluorescence, NMR), thermal denaturation of the double coil, microcalorimetry. Possibilities and examples of a rational approach to the design of new drugs based on the recognition of structural features and sequences of nucleic acids: RNA meta in the design of new antiviral drugs; bleomycini; the design of organic molecules for binding to HIV RNA; inhibitors of Tat-TAR interaction; new platinum anticancer drugs; dictional antimicrobial agents that bind into the DNA groove; intercalation and cytotoxicity; new drugs based on DNA inhibition of topoisomerase.
Experimental work: determination of constants and ways of binding selected molecules to polynucleotides using UV and fluorescence spectroscopy and thermal denaturation. Examples of analyses of complex systems by a multivariate regression method (ligand, DNA / RNA and several of their different complexes present at the same time).

1. Analyze the design of new antitumor and antiviral drugs based on the recognition of structural features of DNA and RNA.
2. Establish the basic principles of operation of a number of methods for examining the interactions of drugs with DNA and RNA.
3. Review the pros and cons of medicinal products operating through DNA/RNA on the basis of relevant literature allegations.
4. Propose the performance of basic experiments for determining interactions in isolated drug-DNA or RNA systems.

In order to successfully master the goals of this subject, the student should regularly attend classes and follow the literature in the field.

Bischoff, G., and Hoffmann, S. (2002) DNA-Binding of Drugs Used in Medicinal Therapies, Curr Med Chem 9, 321-348.
Small Molecule DNA and RNA Binders, Vol. I and II; M. Demeunynck, C. Bailly and W. D. Wilson ED.'s, Wiley-VHC, 2002.
W. Saenger, "Principles of Nucleic Acid Structure, Springer-Verlag, 1984.
E. García-España, I. Piantanida, H-J Schneider,; Book Series: Monographs in Supramolecular Chemistry Volume: 13, Supramolecular systems in biomedical fields / Chapter 8: Nucleic acids as supramolecular targets; Hans-Jörg Schneider (Ed.).; London : Royal Society of Chemistry, 2013 pp. 213-259.
P.B. Dervan "Molecular Recognition of DNA by Small Molecules, Bioorg. Honey. Chem., 2001, 9, 2215-2235.
R.M. Wadkins, Targeting DNA Secondary Structures, Curr. Honey. Chem. , 2000, 7, 1-15.
C. Bailly, Topoisomerase I Poisons and Supresors as Anticancer Drugs. Curr. Honey. Chem. , 2000, 7, 39-58.

J. Matic, L.-M. Tumir, M. Radić Stojković, I. Piantanida, "Advances in peptide-based DNA/RNA-intercalators" Curr. Protein & Peptide Sci. 17 (2016) 127-134.
L.-M. Tumir, M. Radić Stojković, I. Piantanida; "Come-back of phenanthridine and phenanthridinium derivatives in 21st century", Beilstein J. Org. Chem. 10, (2014), 2930–2954.
Ali, A., and Bhattacharya, S. DNA binders in clinical trials and chemotherapy, Bioorg. Honey. Chem. 22, (2014) 4506–4521
L.-M. Tumir, I. Piantanida; "Recognition of Single Stranded and Double Stranded DNA/RNA Sequences in Aqueous Medium by Small Bis-Aromatic Derivatives", Mini-Rev. in Med. Chem., 10 (2010) 299-308

Verification of the understanding of the information obtained, the method of presentation and the scope of the material adopted by using the questionnaire at the end of the lecture of the subject.
Discussions with students and colleagues.
The success of the course will be evaluated every year by the study leadership and the joint expert committee of the institutions of the holders of the study.