Verdine Laboratory

The research interests of the Verdine lab lie in the emerging area of chemical biology. We study biologic processes underlying growth and proliferation of human cancer cells, control of gene expression, and preservation of genomic integrity.

Our research has led to the invention of new and powerful approaches for the discovery of unconventional bioactive ligands termed "synthetic biologics" that have proven effective at addressing therapeutic targets previously considered "undruggable." Verdine and coworkers have elucidated the mechanism by which DNA methyltransferases catalyze epigenetic modification of the genome, as well as the structural basis for sequence specific DNA recognition by NF-κB and NFAT, master regulators of acute phase and immune responses and organ development.

Our work has illuminated the biochemical and structural basis for enzymatic recognition and removal of mutagenic damage in DNA.

See also: Cancer, Lab

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Research

Peptide Stapling

Nearly all FDA-approved molecules fall into one of two established classes of drugs: small molecules and biologics. Members of each class, however, suffer from fundamental physical limitations that necessarily restrict their operating range. Small molecules can target only the ~10% of human proteins that bear a hydrophobic pocket on their surface, whereas biologics can target only the ~10% that are accessible via the cell exterior. Due to significant overlap of these slices of the proteome, it is estimated that ~85% of human proteins reside within the cell and lack a hydrophobic pocket, causing them to be “undruggable” by either established therapeutic modality. As accumulated functional and genomic information has irrefutably linked certain undruggable targets with causation of human disease, the development of novel therapeutic modalities that can access these undruggable targets is becoming increasingly important to the future of medicine.

The Verdine Lab has pioneered a conformational stabilization technology, termed all-hydrocarbon peptide stapling, which induces unstructured peptides to adopt a bioactive α-helical structure. These all-hydrocarbon stapled peptides display the ability to bind to biological targets with affinities in the nanomolar to picomolar range; feature substantial resistance to degradation by proteases; and penetrate the cell membrane through endocytic vesicle trafficking; and are capable of inhibiting disease-relevant protein-protein interactions in vivo. Our laboratory has reported all-hydrocarbon stapled peptide inhibitors of some of the most challenging biological targets: the anti-apoptotic protein BCL-2, the NOTCH transcription factor complex, the E3 ubiquitin ligase HDM2, and the β-catenin transcription factor.

We are currently interested in not only applying all-hydrocarbon stapled peptide technology to the development of α-helical agonists or antagonists of a wide variety of proteins, including Ras and the insulin receptor, but we are also interested in using all-hydrocarbon peptide stapling technology to stabilize tertiary structures such as helix-turn-helix or α/β motifs. Another current area of research in the laboratory is development of novel peptide stapling strategies that will allow us to build upon the promising biological results observed for the all-hydrocarbon peptide stapling technology.

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Protein Catalysis on DNA

Every organism from parasitic viruses to humans must maintain the integrity of its genome in order to successfully propagate. The accurate transfer of genetic material to successive generations in the form of DNA is the ultimate goal of all living entities. DNA, like any chemical, is subject to a wide variety of covalent modifications including: alkylation, oxidation, hydrolysis and reduction. These lead to mutations causing changes in the genetic code. In order to prevent such changes, all organisms actively scan their DNA searching for damage and restoring the correct base. Our laboratory is interested in the study of enzymes involved in the chemical recognition and repair of damaged DNA. The base excision repair glysosylases are one class of repair enzymes. This family of mechanistically related enzymes scans the genome looking for particular subsets of base damage and excises the aberrant base. Also studied are proteins that directly repair alkylated DNA by transferring chemical modification onto the protein. Besides the fascinating questions of chemical recognition and catalysis preformed by these enzymes, the study of DNA repair mechanisms in humans is of interest because of the role of DNA damage to disease and aging. We have developed a comprehensive research program using synthetic chemistry, molecular biology, structural biology and genetics to study this class of proteins in order to gain insights into their role in genomic maintenance.

RNA Targeting

Conventional RNA-directed therapeutic strategies have largely been limited toward sequence-based targeting of protein-coding messenger RNAs. RNA biology, however, expands far beyond protein coding, and RNA is a key component in an ever-expanding list of cellular processes. Furthermore, it has become increasingly clear that the folded structures of RNAs are critical to their diverse functions. Thus, any strategy limited to mRNA primary sequence excludes a vast and rich array of potential therapeutic RNA targets.

Our strategy employs short RNA-Interacting Polynucleotides (RIPtides) as a means for targeting RNAs of interest. Short sequences (8mer or less) allow for unbiased array-based screening, as all permutations of 4mer to 8mer nucleotides may be synthesized in an array and assayed for binding the RNA of interest. Using screening conditions that allow for RNA secondary structure formation, we identify sequences capable of binding a folded RNA structure, rather than relying on a primary sequence with regions that may not be available for binding upon folding. In addition, unbiased screening leaves open the possibility of non-canonical base-pairing not predicted by primary sequence alone. With these lead sequences, we take a multi-pronged chemical biology approach that incorporates strategies for chemical modification to increase RNA stability and membrane permeability, while closely investigating the biological impact of the discovered RNA-binding sequences.

Teaching

2016-2017 FALL

SCRB 192

Principles of Drug Discovery and Development

Co-Instructor: Anthony Wood, Head of Worldwide Medicinal Chemistry, Pfizer
Days/Time: Mondays, Wednesdays 2:30-4:00 PM

Location: TBA (probably Northwest Laboratory Lecture Hall B-101)

This interdisciplinary course will examine the process of drug discovery and development through disease-driven examples. Topics include: the efficacy/toxicity balance, the differences between drugs and inhibitors, the translation of cellular biochemistry to useful medicine.

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