Chemistry: Faculty Directory

The Disney group develops rational approaches to design selective therapeutics from only genome sequence. One of the major advantages that genome sequencing efforts potentially provides is advancing patient-specific therapies, yet such developments have been only sparsely reported. We have developed general approach to provide lead Targeted Therapeutics and Precise Medicines that target RNAs that cause disease broadly and include rare neuromuscular (muscular dystrophy), neurodegenerative (Alzheimer’s, ALS), infectious diseases as well as difficult-to-treat cancers (breast, pancreatic, prostate, and others), and infectious diseases that can emerge through seasonal exposures. Designed compounds have demonstrated activity in human derived cellular disease models as well as pre-clinical animal models of disease. We train the next-generation of scientists to ensure our work has an exponential impact in studying disease biology and leveraging it into making Precision Medicines.

To achieve these goals, we developed a proprietary platform dubbed Inforna over the past 13 years. It merges chemoinformatics and RNA structure to identify lead compounds that target an RNA of interest; that is, Inforna houses a database of RNA three dimensional motifs that bind small molecule medicines, identified via an experimental library-versus-library screen. The bioinformatics pipeline rapidly and accurately identifies disease-associated RNA sequences that adopt targetable three-dimensional folds by comparison to the database. This pipeline has been validated in various peer-review publications that demonstrated that the platform can be used to target RNAs that cause neuromuscular, neurodegenerative, and infectious diseases as well as difficult-to-treat cancers in pre-clinical animal models. Additionally, lead small molecule medicines can also be rapidly developed into compounds that recruit cellular nucleases to selectively destroy the RNAs that cause these diseases in a catalytic and substoichiometric manner (e.g. one molecule of the small molecule cleaves more than one molecule of the RNA target) coined RIBOTACs. Two of the major perceived concerns in the area of RNA-targeted small molecules are selectivity and potency. We have broadly demonstrated that these issues can be rapidly overcome via rational design and fragment assembly.

Key recent advances include:

(i) Sequence-based drug design across the human transcriptome to provide precision lead medicines

(ii) Small molecule cleavage of RNAs (RIBOTACS) in a catalytic and sub-stoichiometric manner via recruitment of cellular nucleases

(iii) Tools and technologies to study ligand binding capacity of RNAs across the transcriptome (Chem-CLIP and Ribo-SNAP)

(iv) Showing broad classes of known drugs target RNA and that their activity may be traced to targeting non-coding RNA

(v) Chemical biology approaches to understand RNA biology. We uncovered the mechanistic cause of Fragule X-Syndrome and Autism and also can define precisely the effect that non-coding RNAs have on the proteome.

(vi) Study druggability broadly. We have the ability to answer fundamental questions about how druggable the genome really is. Thus, we have launched the Druggable Transcriptome Project.

The Kodadek laboratory works in the general area of chemical biology with an emphasis on translational research. The laboratory employs a broad spectrum of techniques that span organic chemistry to molecular genetics. Recently, significant effort has been focused on the development of novel strategies to tackle the “undraggable” proteome. We have developed DNA-encoded libraries of non-peptidic macrocycles and other novel molecular species that we believe will be better suitable to engage difficult protein targets than traditional drug candidates. We are also developing novel techniques to screen these libraries for molecules with novel functions, for example the ability to recruit to target proteins post-translational modifying enzymes that alter the levels or activity of the target.

Another focus is to use the chemical tools we have developed to monitor and manipulate the immune system. One goal of these efforts is to discover effective and early diagnostic tests for a variety of disease states, including cancers, autoimmune diseases and neurodegenerative conditions. Another is to identify compounds that act as “antigen surrogates” in that they have the ability to recognize the antigen-binding sites of antibodies and T cell receptors. These compounds are being developed as potential therapeutic agents to block autoimmune responses selectively without interfering with normal functions of the immune system.

Design and Study of Molecular Catalysts for Small Molecule Conversion

CH4 (and other light alkanes in Natural Gas), N2, O2, H2O and CO2 are among the most abundant raw materials on Earth. Chemical reactions of these small molecules generate most of the world’s energy, emissions and materials. However, in spite of a century of research, current technologies still operate at higher costs, generate substantially more emissions and lead to greater dependence on petroleum than required. At the foundation of these inefficiencies is the high strength of the bonds in all of the small molecules. In spite of intensive effort over more than 50 years, failure to develop chemistry to controllably make and break these bonds has led to the unfortunate assignment of these small molecule challenges as “Holy Grails” in chemistry. The focus of our research is to overcome these challenges through the design of next generation catalysts for the direct, selective, conversion of these molecules. One particular emphasis continues to be the design of systems that will enable the direct conversion of alkanes to fuels and chemicals at lower temperatures. This could replace or augment the use of petroleum with cleaner, more abundant Natural Gas as a transition to a cleaner future. Our approach is based on the rational, de novo design of molecular (s-called homogeneous or single-site) catalysts through an iterative process involving conceptual design, computational study, synthesis, characterization and study of reaction chemistry and mechanisms. Our research interests include the design of catalysts for: CH hydroxylation; CH aminations, N2 fixation, O2 activation and CO2 reduction.

A critical component of the development of new medicines is the identification and validation of new protein targets. Our laboratory is focused on using state-of the-art methods in chemical biology to discover new therapeutically relevant protein-biomolecule interactions that contribute to disease.

Natural Product Biosynthesis, Engineering, and Drug Discovery. Microorganisms produce a large variety of biologically active substances representing a vast diversity of fascinating molecular architecture not available in any other systems. Our research centers on the chemistry, biochemistry and genetics of the biosynthesis of these secondary metabolites. Blending organic chemistry, biochemistry, and molecular biology, we take a multidisciplinary approach to study the secondary metabolism by asking the following questions: what reactions are available in nature, what are the enzymatic mechanisms of these reactions, how are these reactions linked to produce complex structures, what are the regulatory mechanisms of these pathways, and, ultimately, how can we leverage a large microbial strain collection and develop enabling genome mining and synthetic biology technologies for natural product discovery and production, and manipulate nature’s biosynthetic machinery for the discovery and development of new drugs. Members of our group gain broad training spanning organic chemistry, biochemistry, microbiology and molecular biology, a qualification that is becoming essential for the modern bioorganic chemists who seek career opportunity in both academia and pharmaceutical and biotechnology industry (http://www.scripps.edu/shen/).

Natural Products Discovery Center at Scripps Research. Natural products are significantly underrepresented in current small molecule libraries. The current Natural Products Library (NPL) at Scripps Research’s Natural Product Discovery Center consists of: (i) purified natural products with fully assigned structures, (b) MPLC (on C-18 semipreparative column) fractions, and (c) crude extracts. The NPL is presented in 384-well format with all materials dissolved in DMSO (1 mM for pure compounds and 50 mg/mL for fractions and extracts), compatible with most of the HTS platforms. The NPL currently available for screening includes: (a) ~600 pure natural products, (b) ~53,500 MPLC fractions, (c) ~205,000 crude extracts. The NPL provides an unprecedented molecular diversity to screen emerging targets for drug leads, and selected members of the NPL serves as outstanding small molecule probes to interrogate biology. Central to the Natural Products Discovery Center is the large microbial strain collection, containing a total of 217,352 bacterial and fungal strains, of which 62,328 are actinobacteria, 14,465 other bacteria, 92,225 fungi, and 48,334 unidentified (bacteria or fungi). Promising leads could therefore be produced in sufficient quantities by microbial fermentation for follow up studies and, ultimately, clinical development.

Diseases caused by bacteria from the genus Mycobacterium afflict humankind for millennia and currently represent a significant source of mortality and morbidity. Examples are human tuberculosis, leprosy, Buruli ulcer and other soft-tissue and lung infections. Tuberculosis alone is still responsible for 1.5 million deaths annually. The increased prevalence of antibiotic resistance in mycobacteria is a significant problem, causing nearly untreatable infections. The Carvalho group is interested in defining how soil-dwelling and water-born mycobacteria became adapted to the human host, a pre-requisite for a human pathogen. In particular, our group is focused on understanding how mycobacterial metabolism and chemistry evolved in the last 50 million years, to allow for optimal growth and virulence in humans. Once these processes have been mapped and characterized at cellular and molecular levels, we will employ state-of-the-art methods, some of which have been pioneered at UF Scripps, to discover and develop novel small molecules capable of killing these pathogens and transform the therapy of tuberculosis and other mycobacterial diseases.

Key recent advances include:

(i) discovery of the first example of target-mediated antibiotic inactivation

(ii) identification of the metabolic requirements for pyruvate and lactate utilization by M. tuberculosis

(iii) discovery of itaconate catabolism in M. tuberculosis and its intersection with amino acid metabolism

(iv) carried out the first fine mapping of nitrogen metabolism in M. tuberculosis.

(v) demonstration of the crucial role of metabolism in bacterial L-form

(vi) discovery of the first NAD+ phosphorylase and its role in M. tuberculosis cell death

Preparation of various organic compounds of synthetic, biological, and medicinal significance in a cost-effective, efficient, reliable and selective manner is vital to advances in human health care. The central theme of the Wasa research program is the development of synthetic methods that possess these desirable attributes and allow rapid access to the important molecules from an array of readily accessible but otherwise chemically inert starting materials.

Synthesis of a target molecule can often be accelerated through the use of a catalyst system; the catalysts facilitate the union of poorly reactive starting materials by converting them into a set of highly reactive intermediates en route to the products. Nonetheless, key shortcomings limit the application of catalytic methods in complex molecule synthesis. Among the critical unresolved issues in the state-of-the-art is the catalyst deactivation, occurring through the formation of stable adducts within a reaction mixture of the catalysts, starting materials, intermediates and/or products. Such process can either result in deceleration or termination of the target reaction. To suppress catalyst deactivation, the range of starting materials is confined to those that pose minimum risk of generating the inert adducts.

The aim of our research team is to address these problems through the design and development of highly efficient and multi-functional catalyst systems that cannot be easily disabled/quenched. We aspire to demonstrate that our catalysts may be used for direct conversion of complex natural products, pharmaceuticals, and agrochemicals to a variety of derivatives of interest.