个人简介

Ph.D.: Yale University (2004) Postdoc: University of Pennsylvania School of Medicine (2004 - 2007)

研究领域

Bio-Organic & Bio-Inorganic Cell Signaling Chemical Biology/Genetics Membranes Biophysics Proteins & Enzymology

Drug Discovery: Potential Therapeutics that Inhibit Toll-like Receptors. Pain remains a significant public health issue with two-thirds of patients achieving little to no pain relief from the myriad of currently available pharmacotherapies and dosing regimens. The use of opioid (e.g. morphine) pharmacotherapies produces several rewarding and reinforcing side effects, which result in the drugs’ diversion to abuse settings. Glial cells have been found to play a critical role in initiating and maintaining increased nociception in response to peripheral nerve injury. The opioids-induced glial cell activation attenuates opioid-induced pain suppression and enhances the development of opioid tolerance and dependence, the drug reward, and other negative side effects such as respiratory depression. We are interested in employing structure-based drug design and high-throughput screening techniques to identify novel small-molecule inhibitors of TLR4 that regulates glial cell activation. The identified agents will potentially serve as therapeutics that suppresses opioid-dependence and tolerance. Using this method, we also successfully identified small molecule inhibitors that disrupt the TLR3-dsRNA interactions. This is significant because the protein-RNA complex is a challenging target for small molecule probes. Our goal is to develop a generally applicable method to provide small molecule probes for the protein-protein and protein-RNA interactions of these clinically relevant TLRs. Protein Engineering: Peptides Targeting Transmembrane Domains of Proteins. Protein transmembrane domains (TMDs) regulate many pivotal biological processes, including cell signal transduction, cancer development, ion transmission, and membrane protein folding. However, the molecular recognition in membranes is little understood due to the lack of available probes with high affinity and specificity. Conventional tools such as antibodies are unable to bind to the transmembrane regions of membrane proteins. A second project in our lab is to develop exogenous peptide and small-molecule agents that target transmembrane helices. Using these agents, we can study these important membrane protein-protein interactions, thereby further our understanding of molecular recognition in membranes. As a proof-of-principle, we developed novel peptide/peptidomimetic reagents to recognize the TMDs of latent membrane proteins 1 (LMP-1) found in the human Epstein-Barr herpesvirus lymphomas and syndromes. These designed peptides will be used to study TMD-mediated LMP-1 activation. The findings from these studies will lay the groundwork for the discovery of new pharmaceutical agents with which we can prevent, diagnose, and treat herpesvirus-dependent cancers. Biotechnology Development: Non-invasive Cancer Biomarkers. Elevated microvesicle (MV) shedding is an indication of cancer metastasis. Sensing their highly curved membrane may provide a novel strategy to detect these MVs, which renders potentials of developing diagnostic, prognostic, and therapeutic agents. We employed a multidisciplinary approach, utilizing our expertise in computational modeling, membrane biophysics, and cellular assay development to rationally design novel tools that sense and regulate membrane curvature and lipid components. These rationally designed agents not only help us to understand the critical protein-lipid interactions but also provide prototypes that may eventually lead to novel cancer biomarkers.

近期论文

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Yin, H.; Flynn, A.D. “Drugging Membrane Protein Interactions”, Annu. Rev. Biomed. Eng. 2016, 18, 51-76. Yan, L.; Liang, J.; Yao, C.; Wu, P.; Zeng, X.; Cheng, K.; Yin, H. “Pyrimidine Triazole Thioether Derivatives as Novel TLR5/Flagellin Complex Inhibitors”, 2016, 11, 822-826. Wang, T.; de Jesus, A.; *Shi, Y.; Yin, H.; “Pyridoxamine is a substrate of the energy-coupling factor transporter HmpT", Cell Discov. 2015, 1, 15014. Daniele, S. G.; Beraud, D.; Davenport, C.; Cheng, K.; Yin, H.; *Maguire-Zeiss, K. A.; “Activation of MyD88-Dependent TLR1/2 Signaling by Misfolded α-Synuclein, a Protein Linked to Neurodegenerative Disorders”, Sci. Signal. 2015, 8, ra45. Cheng, K.; Gao, M.; Godfroy, J. I. III; Brown, P. N.; Kastelowitz, N.; Yin, H.; “Specific Activation of the TLR1-TLR2 Heterodimer by Small-molecule Agonists”, Sci. Adv. 2015, 1, e1400139. Smith, C. E.; Wang, X. H.; Yin, H.; “Caspases Come Together Over LPS”, Trends Immunol. 2015, 36, 59-61. Yang, H.; Chen, Y. Z.; Zhang, Y.; Wang, X. H.; Zhao, X.; Godfroy, J. I.; Liang, Q.; Zhang, M.; Zhang, T.; Yuan, Q.; Royal, M. A.; Driscoll, M.; Xia, N. S.; Yin, H.; Xue, D. “A Lysine-Rich Motif in the Phosphatidylserine Receptor PSR-1 Mediates Recognition and Removal of Apoptotic Cells”, Nat. Commun. 2015, 6, 5717. Csakai, A.; Smith, C.; Davis, E.; Martinko, A.; Coulup, S.; Yin, H. “Saccharin Derivatives as Inhibitors of Interferon-Mediated Inflammation”, J. Med. Chem. 2014, 57, 5348-5355. Wang, X. H.; Grace, P. M.; Pham, M. N.; Cheng, K.; Strand, K. A.; Smith, C. E.; Li, J.; Watkins, L. R.; Yin, H. “Rifampin Inhibits Toll-like Receptor 4 Signaling by Targeting Myeloid Differentiation Protein 2 and Attenuates Neuropathic Pain”, FASEB J. 2013, 27, 2713-2722. Wang, X. H.; Smith, C.; Yin, H. “Targeting Toll-Like Receptors with Small Molecule Agents”, Chem. Soc. Rev. 2013, 42, 4859-4866. Brown, P. N.; Yin, H. “PNA-Based MicroRNA Inhibitors Elicit Anti-Inflammatory Effects in Microglia Cells”, Chem. Commun. 2013, 49, 4415-4417. Morton, L. A.; Saludes, J. P.; Beninson, L.; Chapman, E. R.; Fleshner, M.; Yin, H. “MARCKS-ED Peptide as a Membrane Curvature Sensor”, ACS Chem. Biol. 2013, 8, 218-225. Cheng, K.; Wang, X. H.; Zhang, S.; Yin, H. “Discovery of Small-Molecules that Inhibit the Protein Complex of Toll-Like Receptor 1 and 2”, Angew. Chem. Int. Ed. 2012, 51, 12246-12249. Saludes, J. P.; Morton, L. A.; Ghosh, N.; Beninson, L.; Chapman, E. R.; Fleshner, M.; Yin, H. “Detection of Highly Curved Membrane Surfaces Using a Cyclic Peptide Derived from Synaptotagmin-I”, ACS Chem. Biol. 2012, 7, 1629-1635. Wang, X. H.; Loram, L. C.; Ramos, K.; de Jesus, A.; Thomas, J.; Cheng, K.; Reddy, A.; Somogyi, A. A.; Hutchinson, M. R.; Watkins, L. R.; Yin, H. “Morphine Activates Neuroinflammation in a Parallel Manner to Endotoxin”, Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 6325-6330. Chavez, S. A.; Martinko, A. J.; Lau, C.; Pham, M. N.; Cheng, K.; Mollnes, T. E.; Yin, H. “Development of β–Amino Alcohol Derivatives that Inhibit TLR4-Mediated Inflammatory Response as Potential Antiseptics”, J. Med. Chem. 2011, 54, 4659-4669. Cheng, K.; Wang, X. H.; Yin, H. “Small Molecule Inhibitors of the TLR3/dsRNA Complex”, J. Am. Chem. Soc. 2011, 133, 3764-3767. Slivka, P. F.; Wong, J.; Caputo, G. A.; Yin, H. “Peptide Probes for Protein Transmembrane Domains”, ACS Chem. Biol. 2008, 3, 402-411. Yin, H. “Exogenous Agents that Target Transmembrane Domains of Proteins”, Angew. Chem. Int. Ed. 2008, 47, 2744-2752. Yin, H.; Slusky, J. S; Berger, B. W.; Walters, R. S.; Vilaire, G.; Litvinov, R. I.; Lear, J. D.; Caputo, G. A.; Bennett, J. S.; DeGrado, W. F. “Computational Design of Peptides that Target Transmembrane Helices”, Science 2007, 315, 1817-1822.