Nucleic acids have proven to be viable targets for small molecule drugs. While many examples of such drugs are detailed in the literature, only a select few have found practical use in a clinical setting. These currently employed nucleic acid targeting therapies suffer from either debilitating off-target side effects or succumb to a resistance mechanism of the target. The need for new small molecules that target nucleic acids is evident.
However, designing a novel drug to bind to DNA or RNA requires a detailed understanding of exactly what binding environments each nucleic acid presents. In an effort to broaden this knowledge, the work presented in this thesis details the binding location and affinity of known and novel nucleic acid binding small molecules with targets ranging from simple RNA secondary structure all the way to the complex structure of ribosomal RNA. Specifically, it is shown that the anthracycline classes of antineoplastics prefer to bind at or near mismatch base pairs in both physiologically relevant iron responsive element RNA hairpin constructs as well as DNA hairpin constructs presenting mismatched base pairs.
Also characterized in this thesis is a novel class of topoisomerase II / histone deacetylase inhibitor conjugates that display a unique affinity for DNA over RNA. Finally, the novel class of macrolide-peptide conjugates, known as peptolides, is shown to retain potent translation inhibition of the prokaryotic ribosome and identification of a novel binding site for the anthracycline class of drugs and the characterization of the two novel drug designs presented in this thesis will undoubtedly aid in the effort to design and discover new molecules that aim for nucleic acid targets.
Table of Contents
Introduction
RNA Structural Motifs Involved in Binding
Targeting the Ribosome
Research Objectives and Topics
The research explores the interaction between small molecule drugs and nucleic acid targets, specifically focusing on how understanding these molecular environments can improve drug design. It investigates binding sites within DNA and RNA, addresses the structural challenges of targeting these molecules, and analyzes the mechanisms of existing therapeutics that exploit nucleic acid binding.
- Binding affinities of small molecules to DNA and RNA structures
- Structural characteristics and binding motifs of nucleic acids
- Mechanisms of action for nucleic acid targeting antibiotics
- Development of novel drug conjugates for translational inhibition
Excerpt from the Book
RNA Structural Motifs Involved in Binding
In recent decades, nucleic acids have been shown to be not merely the scribes of the genetic and proteomic code, but they have also been revealed to play crucial roles in regulating genes and gene products via interaction with a variety of ligands including other nucleic acids, proteins, metabolites, cofactors, enzymes, and small molecules (1-11). Prior to this realization, proteins were the main targets of a medicinal chemistry campaign to identify novel small molecules with therapeutic potential. With the successful sequencing of the human genome, hopes were high that all proteins in the human body could be identified and subsequently many new ones could become the target for the treatment of diseases. This, however, has not panned out as only 15% of the human proteome has been deemed drugable and only 207 proteins are targeted by current FDA approved small molecule drugs (12, 13).
Many of these clinically successful drugs share the trait of mimicking a protein partner in a protein-protein interaction as their primary mode of action (14, 15). Due to the large surface area and relative complexity of these interactions, it has proven to be a very difficult endeavor to target proteins with small molecules for therapeutic application. This has emphasized the importance of being able to target the source of the protein product related to a disease state, the DNA and RNA encoding it, as a means of treatment. There have been relatively few successful cases of directly targeting DNA in a clinical setting. The most notable success stories would be the alkylating antineoplastic agents such as nitrogen mustards, nitrosoureas, and alkyl sulfonates as well as the cisplatin and anthracycline families of chemotherapeutics (16-19). With an even more underwhelming representation is the effort to develop treatments exploiting RNA as the target, excluding of course ribosomal RNA-targeting antibiotics.
Summary of Chapters
Introduction: This chapter contextualizes the shift from protein-targeted drug discovery to nucleic acid targets, highlighting the limitations of current medicinal chemistry in drugable proteome space.
RNA Structural Motifs Involved in Binding: This section examines the secondary and tertiary structural complexities of RNA, such as hairpins and junctions, and explains how these motifs create specific binding environments for small molecules.
Targeting the Ribosome: This chapter details the structure and function of the bacterial ribosome as a primary clinical target, analyzing how antibiotics like linezolid and macrolides interact with the peptidyl transferase center to inhibit protein synthesis.
Keywords
Messenger RNA, DNA, Ribosomal RNA, SAR, Anthracyclines, Cisplatin, Ribozymes, tRNA, Antibiotics, Linezolid, Macrolides, Protein Synthesis, Translational Inhibition, Binding Affinity, Peptidyl Transferase Center
Frequently Asked Questions
What is the primary focus of this thesis?
The work primarily focuses on broadening the knowledge of how small molecule drugs bind to DNA and RNA, aiming to assist in the rational design of new therapeutic agents that target nucleic acids.
What are the central research themes?
The research revolves around nucleic acid structural biology, the biophysics of ligand-nucleic acid interactions, and the pharmacodynamics of existing and novel drugs that target these molecules.
What is the core research objective?
The objective is to characterize binding preferences in nucleic acids and explore how structural motifs, such as mismatch base pairs in RNA, can be utilized to develop more effective, targeted therapies.
Which scientific methodology is employed?
The thesis utilizes structural biology analysis, including the examination of crystal structures, and incorporates rational drug design principles to investigate binding affinities and target validation.
What topics are covered in the main body?
The main body covers the structural differences between DNA and RNA, the formation of complex secondary/tertiary RNA structures, and a detailed look at how ribosomal RNA is targeted by specific antibiotic families.
Which keywords define this work?
Key concepts include nucleic acid stability, RNA structural motifs, translational inhibition, ribosomal targeting, and small molecule design.
How does the secondary structure of RNA influence small molecule binding?
Unlike the more uniform structure of B-DNA, RNA folds into complex, diverse shapes including bulges and stem junctions, which create unique electronegative pockets that provide specific binding sites for small molecules.
Why is the ribosome considered a vital target?
The ribosome is the essential protein-production machinery for all life forms; targeting its rRNA components with small molecules allows for the disruption of protein synthesis, which serves as a highly effective mechanism for antibiotics.
What role does rRNA methylation play in drug resistance?
Bacterial resistance to drugs like macrolides often involves the methylation of specific residues (such as A2058) within the rRNA. This modification sterically hinders the drug from binding to its designated pocket in the ribosome, thereby preventing the drug from inhibiting protein synthesis.
- Quote paper
- Kehinde Sowunmi (Author), 2020, Effect of Small Molecules on Nucleic Acid Stability and Improvements to RNA Structure Prediction, Munich, GRIN Verlag, https://www.grin.com/document/594009
