RESEARCH PROJECTS

Research in the Walczak group focuses on creating new tools and strategies to manipulate and understand the function of  (bio)molecules in human health and disease. Most projects are highly interdisciplinary and incorporate computational, biophysical, and molecular biology resources available at CU and through our collaborations to answer the key scientific questions.

Active projects fall into two general categories:

(a) chemical synthesis - methods to prepare and selectively functionalize natural products, saccharides, peptides, and proteins. We are interested in inventing and applying new reactions to eliminate critical synthetic challenges, and our efforts are centered on catalytic methods that can facilitate drug identification and downstream development.  

(b) chemical biology - tools to understand molecular mechanisms of neurodegeneration. We apply our chemical expertise to develop reagents and strategies to dissect the underlying pathological processes involved in Alzheimer's disease, FTD and other tauopathies. 

 

Click on the links below to learn more about our ongoing research:

1. Synthetic Methodology & Glycosyl Cross-Coupling

We have developed a collection of catalytic methods, broadly defined as the glycosyl cross-coupling, that allow for a stereoretentive (as opposed to stereoinvertive) installation of glycosidic bonds. This departure from established mechanistic paradigms in carbohydrate synthesis opens opportunities for predictable and programmable introduction of glycosides in a broad collection of substrates. Our technology is operational for any saccharide supplied in both anomeric configurations. We have been able to  demonstrate the generality of the cross-coupling technology in reactions with free saccharides as well as complex oligosaccharides. We are currently pursuing applications focused on chemical synthesis of bioactive glycoconjugates, bioconjugation, and protein engineering. 

Additional reading: J. Am. Chem. Soc. 2020ACS Cent. Sci. 2018J. Am. Chem. Soc. 2017

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2. Chemical Approaches to Understand Molecular Mechanisms of Neurodegeneration

Neurodegenerative diseases such as Alzheimer's disease represent an enormous socioeconomical burden and require broad collaborative efforts to identify effective treatments. Our main objective is to investigate novel targets and take advantage of high precision of chemical synthesis to test mechanistic hypotheses in in vitro models (e.g., hiPSC-derived neurons). These studies encompass the development of (bio)chemical  tools to control biomolecular condensation and efforts to understand molecular underpinnings of interneuronal spread of toxic species and disease-related changes in proteostasis. 

Specific research questions:

  • How do molecular features impact protein aggregation and how can we reconstitute these processes in vitro?

  • How do post-translational modifications impact liquid-liquid phase separation (LLPS) of proteins and can we control in vitro/in vivo LLPS with spatiotemporal precision?

  • What are the molecular determinants that affect protein degradation in AD and other tauopathies?

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3. Thiopeptides & Discovery of Novel Anti-infective Agents

Thiopeptides are post-translationally modified peptides with potent anti-bacterial activities but unrealized clinical potential. We have developed a general approach to access selected members of this family. Our approach capitalizes on cyclodehydration of cysteine residues using a novel molybdenum-based catalyst or cyclic phosphonium anhydrides. With these methods in hand, we were able to complete total syntheses of representative thiopeptide antibiotics and study their biological properties. 

In addition to thiopeptides, we actively pursue other targets with validated biological activities. These studies are highly interdisciplinary and involve collaborations with microbiologists, chemical biologists, and medicinal chemists.

 

Additional reading: Chem. Sci. 2019; ACS Catal. 2022; Angew. Chem. Int. Ed. 2022

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4. Synthetic Protein Assemblies

Synthetic chemistry opens unprecedented opportunities to create and modify complex molecular scaffolds. We design and manufacture protein assemblies that address some of the most challenging problems in gene and drug delivery. Specifically,  we prepare macromolecular peptides and protein structures with improved stabilities and low immunogenicity suitable for therapeutic and diagnostic applications. These synthetic proteins are inspired by natural structures but underwent substantial modifications to achieve the desired functions. 

 

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