SMALL-MOLECULE AND NUCLEIC ACID ENGINEERING TOWARD MOLECULAR DESIGNS OF THERAPEUTIC POTENTIAL

PROJECT SUMMARY / ABSTRACT Designer small molecules and nucleic acid polymers are essential to the advancement of biotechnology and precision medicine. However, efforts to develop such molecules with therapeutic potential face significant challenges with regard to target selectivity, efficacy, and biostability. These challenges present critical barriers

to progress in clinical applications. Our long-term goal is to address these challenges by combining synthetic organic chemistry and nucleic acid engineering toward sophisticated molecular designs as modulators of disease-related targets or pathways. To achieve our goal, we propose the following research programs in this

MIRA application: 1) We will develop novel ligand-heterocycle conjugates as high-performing targeted RNA degraders. These conjugates will exhibit rapid RNA degradation kinetics along with excellent selectivity for G-quadruplexes found in RNAs associated with cancer; 2) We will engineer nucleic acid polymers with

(thio)phosphoramidate backbones that can serve as biostable mimics of RNA-cleaving ribozymes. In addition, we will develop cyclic (thio)phosphoramidate dinucleotides as biostable agonists of the cGAS–STING pathway, a critical mediator of inflammation; and 3) We will enhance the therapeutic potentials of nucleic acid

catalysts (NAzymes) by introducing programmable RNA cleavage functionality. Trans-acting NAzymes that cleave RNA targets will be selectively activated by biochemical agents prevalent in disease conditions, reducing damage to healthy cells. Realization of the proposed design principles will help advance the field of

nucleic acid therapy and drug development efforts geared toward precision medicine. The proposed research projects will establish a foundation for promoting diversity and inclusivity, with opportunities for cross- institutional collaborations and professional development.