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Research Overview
Biochemistry/Chemical Biology/Drug Discovery/Organic Chemistry
Our research spans from mechanistic study of biological phenomena, development of novel methodologies, to applications of the mechanistic understanding and methodologies to discover novel therapeutic agents and chemical probes. It is estimated that ~80% of all disease relevant human proteins are undruggable by current drug modalities, which include small molecules (molecular weight <500) and biologics (molecular weight >5000). Prominent examples of undruggable proteins are those involved in intracellular protein-protein interactions (PPIs) and the defective/missing proteins caused by genetic mutations. The goals of our research are 1) to understand how biomolecules enter the mammalian cell and 2) to develop a general strategy for drugging these challenging targets. The following projects are under current investigation in our group.
Macrocyclic Peptides as Protein-Protein Interaction Inhibitors. Protein-protein interactions (PPIs) represent an exciting but also very challenging class of drug targets, because they usually have large, flat binding sites, to which conventional small molecules do not bind with high affinity or specificity. We and others have demonstrated that macrocyclic peptides in the molecular-weight range of 500-2000 serve as effective PPI inhibitors. We have developed a powerful technology to chemically synthesize and screen large libraries of cyclic and bicyclic peptides (up to 30 million different compounds) against essentially any protein of interest. We are currently applying this technology to discover macrocyclic peptide inhibitors against PPIs involved in human diseases (e.g., cancer, cystic fibrosis, inflammation, and autoimmunity). We are also developing new methodologies to synthesize and screen combinatorial libraries of non-peptidic, natural product-like macrocycles.
Mechanism and Application of Cell-Penetrating Biomolecules. The cell membrane represents a major obstacle in drug discovery, which is particularly problematic for peptide-, protein-, and nucleic acid-based drugs (e.g., siRNA). We have discovered a family of small cyclic peptides such as cyclo(phe-Nal-Arg-arg-Arg-arg-Gln) as powerful cell-penetrating peptides (CPPs), which are capable of efficiently delivering small molecules, peptides, proteins, and nucleic acids into the cytosol of mammalian cells. We discovered that CPPs enter cells by endocytic mechanisms and exit the endosome by a novel vesicle budding-and-collapse mechanism. We have also discovered non-peptidic cell-penetrating motifs (CPMs) that specifically deliver cargo molecules into the mitochondrial matrix. Current studies in this area include the discovery/design of additional CPPs/CPMs with improved properties (e.g., selectivity for cancer cells) and the cellular entry mechanisms of other synthetic drug delivery systems, bacterial toxins, and viruses.
Development of Intracellular Biologics and Chemical Probes. Biologic drugs (e.g., monoclonal antibodies) have transformed the drug industry over the past several decades but are so far limited to extracellular targets. We are leveraging the cyclic CPP technology to develop intracellular biologics as next-generation therapeutics and chemical probes. First, we are developing innovative strategies to use cyclic CPPs to deliver proteins, nucleic acids, and protein-nucleic acid complexes into the cell. Second, we are integrating the ligand discovery and cyclic CPP technologies from above to develop cell-permeable and metabolically stable macrocyclic peptide inhibitors against medicinally important but previously challenging PPI targets, such as calcineurin (inflammation), CAL PDZ domain (cystic fibrosis), MDM2 (cancer), NEMO (cancer and inflammation), and K-Ras (cancer). Finally, we have developed a general approach to engineering cell-permeable proteins by grafting short CPP motifs into their surface loops and are applying this strategy to design therapeutic proteins.
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Sijie Chen,Tong Lin, Ruchira Basu, Jeremy Ritchey,Shen Wang, Yichuan Luo, Xingcan Li,Dehua Pei,Levent Burak Kara,Xiaolin Cheng
Nature Communicationsno. 1 (2024): 1611-1611
JOURNAL OF PEPTIDE SCIENCE (2024)
Journal of peptide science : an official publication of the European Peptide Societypp.e3565-e3565, (2024)
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