Hubert Yin’s research interests lie
at the interface of chemistry and biology with particular
focus on structure-based drug design and membrane protein
1. 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.
2. Protein Engineering: Peptides Targeting Transmembrane Domains of Proteins. Protein transmembrane domains (TMDs) regulate many pivotral 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 proof-of-principle, we developed novel peptide/peptidomimetic reagents to recognize 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.
3. 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.
Multi-Tox: A ToxR-Based Assay for Multi-Pass Transmembrane Domain Oligomerization (2011), Joce, C; Wiener, AA; Yin, H; Biochim. Biophys. Acta. 1808, 2948-2953.
Transmembrane Peptides Used to Investigate the Homo-Oligomeric Interface and Binding Hot-Spot of Latent Membrane Protein 1 (2011), Sammond, DW; Joce, C; Takeshita, R; McQuate, S; Ghosh, N; Martin, JM; Yin, H; Biopolymers95, 772-784 (cover story).
An MD2 Hot-Spot Mimicking Peptide that Suppresses TLR4-Mediated Inflammatory Respnose In Vitro an In Vivo (2011), Liu, L; Ghosh, N; Slivka, PF; Fiorini, Z; Hutchinson, MR; Watkins, LR; Yin, H; ChemBioChem 12, 1827-1831 (cover story).
Small Molecule Inhibitors of the TLR3/dsRNA Complex (2011), Cheng, K; Wang, XH; Yin, H; J. Am. Chem. Soc.133, 3764-3767.
Application of a Novel In Silico High Throughput Screen to Identify Selective Inhibitors for Protein-Protein Interactions (2010), Joce, C; Stahl, JA; Shridhar, M; Hutchinson, MR; Watkins, LR; Fedichev, PO; Yin, H; Bioorg. Med. Chem. Lett. 20, 5411-5413.
Selection, Preparation, and Evaluation of Small-Molecule Inhibitors of Toll-Like Receptor 4 (2010), Bevan, DE; Martinko, AJ; Loram, LC; Stahl, JA; Taylor, FR; Joshee, S; Watkins, LR; Yin, H; ACS Med. Chem. Lett. 1, 194-198.
Toll-like Receptor 4 in CNS Pathologies (2010), Buchanan, MM; Hutchinson, MR; Watkins, LR; Yin, H; J. Neurochem. 114, 13-27.
Development of Agents That Modulate Protein-Protein Interactions in Membranes (2010), Zhao, TX; Martinko, AJ; Le, VH; Zhao, J; Yin, H; Curr. Pharm. Des. 16, 1055-1062.
A Peptide Antagonist of the TLR4/MD2 Interaction (2009), Slivka, PF; Shridhar, M; Lee, GI; Sammond, DW; Hutchinson, MR; Martinko, AJ; Buchanan, MM; Sholar, PW; Kearney, JJ; Harrison, JA; Watkins, LR; Yin, H; ChemBioChem 10, 645-649.
Two Fluorescent Probes to Dissect the Binding, Insertion, and Dimerization Kinetics of a Model Membrane Peptide (2009), Tang, J; Yin, H; Qiu, J; Tucker, M; DeGrado, WF; Gai, F; J. Am. Chem. Soc. 131, 3816-3817.
Design, Synthesis, and Evaluation of Biotinylated Opioid Derivatives as Novel Probes to Study Opioid Pharmacology (2008), Li, Y; Chase, AR; Slivka, PF; Baggett, CT; Zhao, TX; Yin, H; Bioconjug. Chem. 19, 2585-2589.
Computationally Designed Peptide Inhibitors of Protein-Protein Interactions in Membranes (2008), Caputo, GA; Litvinov, RI; Li, W; Bennett, JS; DeGrado, WF; Yin, H; Biochemistry 47, 8600-8606.
Peptide Probes for Protein Transmembrane Domains (2008), Slivka, PF; Wong, J; Caputo, GA; Yin, H; ACS Chem. Biol. 3, 402-411.
Exogenous Agents that Target Transmembrane Domains of Proteins (2008), Yin, H; Angew. Chem. Int. Edit. 47, 2744-2752 (cover story).
Computational Design of Peptides that Target Transmembrane Helices (2007), Yin, H; Slusky, JS; Berger, BW; Walters, RS; Vilaire, G; Litvinov, RI; Lear, JD; Caputo, GA; Bennett, JS; DeGrado, WF; Science 315, 1817-1822.