WALCZAK GROUP AT THE UNIVERSITY OF COLORADO BOULDER
RESEARCH PROJECTS
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The Walczak Lab develops chemical tools and strategies to investigate and manipulate the function of (bio)molecules relevant to human health and disease. Our research is highly interdisciplinary, integrating synthetic chemistry, biophysics, molecular biology, and structural approaches. We leverage both the extensive resources at the University of Colorado Boulder and collaborations across campus and beyond to address fundamental questions in chemical biology and biomedical research.
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Active projects fall into two general categories:
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1. Chemical Synthesis. We design and develop synthetic methods for the preparation and selective functionalization of biologically relevant molecules, including natural products, carbohydrates, peptides, and proteins. Our efforts are focused on overcoming key synthetic challenges using catalytic strategies, with the ultimate goal of enabling drug discovery and development. Areas of interest include:
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Synthesis and site-selective modification of complex biomolecules
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Late-stage functionalization to diversify natural product scaffolds
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Catalysis for bioconjugation and labeling
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2. Chemical Biology of Neurodegeneration. We apply chemical principles to study the molecular underpinnings of neurodegenerative diseases such as Alzheimer’s disease, frontotemporal dementia (FTD), and related proteinopathies. Using custom-designed reagents and probes, we aim to:
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Elucidate mechanisms of protein misfolding and aggregation
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Characterize the role of post-translational modifications
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Develop cell–based models to study disease progression and therapeutic interventions
Click on the links below to learn more about our ongoing research:
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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.
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Additional reading: J. Am. Chem. Soc. 2024; ACS Cent. Sci. 2018; J. Am. Chem. Soc. 2017
2. Chemical Approaches to Understand Molecular Mechanisms of Neurodegeneration
Neurodegenerative diseases, such as Alzheimer’s disease (AD), pose an immense socioeconomic burden and demand collaborative, multidisciplinary approaches to discover effective therapies. Our group aims to identify novel molecular targets and leverage the precision of chemical synthesis to test mechanistic hypotheses in well-defined model systems, including human iPSC-derived neurons.
Our research combines synthetic chemistry, molecular biology, and cell-based approaches to develop new biochemical tools for probing disease mechanisms. We focus on controlling biomolecular condensation, dissecting the molecular basis of interneuronal transmission of toxic protein species, and understanding how proteostasis is disrupted in neurodegenerative conditions.
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Specific research questions:
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How do molecular features impact protein aggregation and how can we reconstitute these processes in vitro?
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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?
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What are the molecular determinants that affect protein degradation in AD and other proteinopathies?
Additional reading: ACS Cent. Sci. 2024, J. Am. Chem. Soc. 2023; ACS Chem. Neurosci. 2023
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.
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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
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.
