Xiaolei Li

Bio: Xiaolei Li is an academic researcher from University of Wisconsin-Madison. The author has contributed to research in topics: Asialoglycoprotein receptor & Oligonucleotide. The author has an hindex of 3, co-authored 3 publications receiving 44 citations.

Development of Triantennary N-Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins

Abstract: Targeted protein degradation (TPD) technology has drawn significant attention from researchers in both academia and industry. It is rapidly evolved as a new therapeutic modality and also a useful chemical tool in selectively depleting various protein targets. As most efforts focus on cytosolic proteins using PROteolysis TArgeting Chimera (PROTAC), LYsosome TArgeting Chimera (LYTAC) recently emerged as a promising technology to deliver extracellular protein targets to lysosome for degradation through the cation-independent mannose-6-phosphate receptor (CI-M6PR). In this study, we exploited the potential of the asialoglycoprotein receptor (ASGPR), a lysosomal targeting receptor specifically expressed on liver cells, for the degradation of extracellular proteins including membrane proteins. The ligand of ASGPR, triantennary N-acetylgalactosamine (tri-GalNAc), was conjugated to biotin, antibodies, or fragments of antibodies to generate a new class of degraders. We demonstrated that the extracellular protein targets could be successfully internalized and delivered into lysosome for degradation in liver cell lines specifically by these degraders. This work will add a new dimension to TPD with cell type specificity.

Site-Selective and Stereoselective O-Alkylation of Glycosides by Rh(II)-Catalyzed Carbenoid Insertion

Abstract: Carbohydrates are synthetically challenging molecules with vital biological roles in all living systems. Selective synthesis and functionalization of carbohydrates provide tremendous opportunities to improve our understanding on the biological functions of this fundamentally important class of molecules. However, selective functionalization of seemingly identical hydroxyl groups in carbohydrates remains a long-standing challenge in chemical synthesis. We herein describe a practical and predictable method for the site-selective and stereoselective alkylation of carbohydrate hydroxyl groups via Rh(II)-catalyzed insertion of metal carbenoid intermediates. This represents one of the mildest alkylation methods for the systematic modification of carbohydrates. Density functional theory (DFT) calculations suggest that the site selectivity is determined in the Rh(II)-carbenoid insertion step, which prefers insertion into hydroxyl groups with an adjacent axial substituent. The subsequent intramolecular enolate protonation determines the unexpected high stereoselectivity. The most prevalent trans-1,2-diols in various pyranoses can be systematically and predictably differentiated based on the model derived from DFT calculations. We also demonstrated that the selective O-alkylation method could significantly improve the efficiency and stereoselectivity of glycosylation reactions. The alkyl groups introduced to carbohydrates by OH insertion reaction can serve as functional groups, protecting groups, and directing groups.

Recent progress in non-native nucleic acid modifications.

Abstract: While Nature harnesses RNA and DNA to store, read and write genetic information, the inherent programmability, synthetic accessibility and wide functionality of these nucleic acids make them attractive tools for use in a vast array of applications. In medicine, antisense oligonucleotides (ASOs), siRNAs, and therapeutic aptamers are explored as potent targeted treatment and diagnostic modalities, while in the technological field oligonucleotides have found use in new materials, catalysis, and data storage. The use of natural oligonucleotides limits the possible chemical functionality of resulting technologies while inherent shortcomings, such as susceptibility to nuclease degradation, provide obstacles to their application. Modified oligonucleotides, at the level of the nucleobase, sugar and/or phosphate backbone, are widely used to overcome these limitations. This review provides the reader with an overview of non-native modifications and the challenges faced in the design, synthesis, application and outlook of novel modified oligonucleotides.

Role of Lipid-Based and Polymer-Based Non-Viral Vectors in Nucleic Acid Delivery for Next-Generation Gene Therapy.

Abstract: The field of gene therapy has experienced an insurgence of attention for its widespread ability to regulate gene expression by targeting genomic DNA, messenger RNA, microRNA, and short-interfering RNA for treating malignant and non-malignant disorders. Numerous nucleic acid analogs have been developed to target coding or non-coding sequences of the human genome for gene regulation. However, broader clinical applications of nucleic acid analogs have been limited due to their poor cell or organ-specific delivery. To resolve these issues, non-viral vectors based on nanoparticles, liposomes, and polyplexes have been developed to date. This review is centered on non-viral vectors mainly comprising of cationic lipids and polymers for nucleic acid-based delivery for numerous gene therapy-based applications.

A heterogeneous iridium single-atom-site catalyst for highly regioselective carbenoid O–H bond insertion

Abstract: Transition-metal-catalysed carbenoid insertion of hydroxyl groups represents a robust and versatile method to forge C–O bonds. Achieving site-selective functionalization of alcohols using this transformation has undoubted synthetic value but remains challenging. Here we report a strategy for selective carbenoid O–H insertion that exploits an engineered heterogeneous iridium single-atom catalyst, thus providing opportunities for organic transformations by merging material science and catalysis. This catalytic protocol delivers excellent selectivities (up to 99:1) for the functionalization of aliphatic over phenolic O–H bonds, whereas the analogous homogeneous catalyst, Ir(ttp)COCl (ttp = 5,10,15,20-tetra-p-tolylporphyrinato), provided modest preferences. Density-functional-theory calculations suggest that the site-selectivity derives from the lower oxidation state of the iridium metal centre in the heterogeneous catalyst and its impact on the absorption energies of the reactants. These results showcase an example of a heterogeneous single-atom catalyst providing superior site-selectivity and provide a complementary strategy to address challenges in catalysis for organic synthesis. Supported single-atom catalysts often feature a distinct reactivity when compared to traditional heterogeneous or homogeneous systems. Here the authors introduce a supported iridium single-atom catalyst for carbenoid O–H insertion characterized by a remarkable selectivity for aliphatic versus aromatic alcohols, unlike its homogeneous counterpart.

Development of Triantennary N-Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins

Abstract: Targeted protein degradation (TPD) technology has drawn significant attention from researchers in both academia and industry. It is rapidly evolved as a new therapeutic modality and also a useful chemical tool in selectively depleting various protein targets. As most efforts focus on cytosolic proteins using PROteolysis TArgeting Chimera (PROTAC), LYsosome TArgeting Chimera (LYTAC) recently emerged as a promising technology to deliver extracellular protein targets to lysosome for degradation through the cation-independent mannose-6-phosphate receptor (CI-M6PR). In this study, we exploited the potential of the asialoglycoprotein receptor (ASGPR), a lysosomal targeting receptor specifically expressed on liver cells, for the degradation of extracellular proteins including membrane proteins. The ligand of ASGPR, triantennary N-acetylgalactosamine (tri-GalNAc), was conjugated to biotin, antibodies, or fragments of antibodies to generate a new class of degraders. We demonstrated that the extracellular protein targets could be successfully internalized and delivered into lysosome for degradation in liver cell lines specifically by these degraders. This work will add a new dimension to TPD with cell type specificity.