Grant: Discovery Grants Program - Individual

Trainees in my lab apply fundamental principles of chemical reactivity to biological molecules such as peptides, oligonucleotides, heterocycles, DNAzymes, and boronates as probes and reagents in biology. We have published competitively in these four disparate areas at the interface of chemistry and biology.***Trainees in my lab i) master aspects of advanced synthetic methods in heteroatom functionalization, ii) develop critical abilities in mechanistic physical organic chemistry, and iii) apply techniques in bioconjugation, molecular biology and combinatorial selection. With these unique skills, trainees attack diverse questions at the interface of chemistry and biology where they synthesize new chemical entities with novel and exciting properties that will create new knowledge while addressing spin-off applications in biotechnology and medicine that test mechanistic hypotheses related to biological processes. Over the past 5 years, we have published work in highly regarded, peer-reviewed journals on: 1) synthetic DNAzymes, 2) physical-organic studies of boronic acids 3) chemical biology of peptide toxins, and 4) synthesis of DNA-inspired ""Janus""-heterocycles for the application of sequence-specific DNA recognition.****The major questions we are pursuing in my lab are the following:*******1) Sequence specific recognition of DNA by synthetic ligands represents an important goal for controlling specific gene expression and investigating DNA structure, function, and accessibility inside cells. New heterocycles are also proposed along with ongoing investigations of Janus-AT/GC nucleosides that recognize a complementary DNA base pair.*******2) Investigation of cyclic peptides where the disulfide bond is replaced to create new biologically active redox-inert peptides. Proposed work on amanitin and phalloidin, hold clues as to fundamental aspects of protein-fold recognition by natural product toxins. Through the synthesis of these toxins, we have identified new bioactivity in two other bioactive peptides as analgesics and growth suppressors.***3) Chemically Modified DNA-based catalysts and aptamers: Nucleic acids represent an exciting technological platform for selecting catalysts and ligands that are capable of medicinally and chemically important transformations, particularly in terms of novel hybrid DNA catalysts that contain protein-like functionalities. These catalysts are useful for RNA cleavage and for sensing. ******4) Organoboronates in biology: We have undertaken fundamental studies of various boronates for reaction with electrophiles and nucleophiles for proto and oxidative deboronation. A major application of this work is 18F-PET imaging which represents a choice imaging modality for preclinical/clinical imaging. We are interested in the fundamental applications of C-B and B-F bond formation for new bioprobes and methods for C-F bond formation. **