Combinatorial Chemistry & High Throughput Screening - Volume 15, Issue 4, 2012

Biomarkers are currently widely used to diagnose diseases, monitor treatments, and evaluate potential drug candidates. Research of differential Omics accelerate the advancements of biomarkers' discovery. By extracting biological knowledge from the ‘omics’ through integration, integrative system biology creates predictive models of cells, organs, biochemical processes and complete organisms, in addition to identifying human disease biomarkers. Recent development in high-throughput methods enables analysis of genome, transcriptome, proteome, and metabolome at an unprecedented scale, thus contributing to the deluge of experimental data in numerous public databases. Several integrative system biology approaches have been developed and applied to the discovery of disease biomarkers from databases. In this review, we highlight several of these approaches and identify future steps in the context of the field of integrative system biology.

Recent advances in high throughput screening technologies have accelerated the identification and characterization of potential factors involved in host-virus interactions, facilitating early detection and diagnosis of diseases, as well as providing promising drug targets. The last decade has seen a plethora of successful examples of high throughput screening approaches, especially siRNA screening. With support from protein interaction studies, mRNA expression profiling, and bioinformatics, siRNA screening has also been successfully utilized to identify host factors required for a number of viruses including HIV, West Nile virus and H1N1 virus. Such studies have raised the awareness of virologists, and have opened a new chapter of global analysis of host-pathogen interactions. However, to play a more defining role in prognostics, diagnostics and therapeutics for virus diseases, acknowledged drawbacks, including false positives and negatives, inherent in this technology, must be successfully addressed.

It has been a very long history for human to resist diseases. During this period, a large number of drugs that could kill or inhibit the growth of microbe has been discovered, most of which were natural products. However, there may still be a large amount of antimicrobial medicines in natural compounds which have not been found yet. The ways of screening for antimicrobial always cost a long time and need a lot of manpower before. However, in recent years, a lot of new antimicrobial targets, antimicrobial drugs and screening methods which are simpler, faster and more efficient have been invented. In this paper the newly discovered targets, natural products and representative technologies were reviewed, which were expected to make some contributions to the research and development of medicines.

Ubiquitylation is a reversible post-translational modification pathway that regulates a variety of cellular processes including protein degradation and trafficking, intracellular localization, DNA repair, immune response and cellcycle progression. Deubiquitylating enzymes (DUBs) can remove the ubiquitin from the modified proteins and reverse the ubiquitylation-induced biological processes; hence it isn't hard to understand that viral pathogens take advantage of the host cell ubiquitin system through disturbing DUBs, for infection and replication. Although accumulated virus-related DUBs have been defined, but how viruses regulate their expression and activities is poor understand because of limitation of technologies. Recently, chemistry-based functional proteomics, which can not only monitor the alteration of abundance but also changes in activity of enzymes, was used to study the function of DUBs involved in virus infection and held much promise. Theses works suggest that chemistry-based functional proteomics is a potent strategy for high throughput screening of virus-related DUBs and exploring their roles in virus infection.

Over the past decade, there have been remarkable advances in the area of computer-aided drug design (CADD), which has been applied at almost all stages in the drug discovery pipeline. The generation of initial lead compounds and the subsequent optimization aimed at improving potency and pharmacological properties are the core activities among all. The development in these aspects over the past years will be the focus of this review.

BIOGRAPHY Prof. Canhua Huang obtained his Ph.D. in Academia Sinica in 2000 and after postdoctoral training at Department of Biological Sciences, National University of Singapore, he was appointed as Research Scientist in Oncology Research Institute, NUS (2003-2005). In Sept 2005, he joined in the State Key Lab of Biotherapy, West China Hospital, Sichuan University, leading a group for oncoproteomics research. RESEARCH INTEREST • High throughput System Biology screening novel drug targets for anti-cancer research. • Mechanisms of virus-induced carcinogenesis; Cancer metabolics and epigenetics. • Chemistry-based functional proteomics for novel drug target deconvolution. SELECTED RECENT PUBLICATIONS [1] Lei, Y.; Huang, K.; Gao, C.; Lau, Q.C.; Pan, H.; Xie, K.; Li, J.; Liu, R.; Zhang, T.; Xie, N.; Nai, H.S.; Wu, H.; Dong, Q.; Zhao, X.; Nice, E.C.; Huang, C.; Wei. Y. Proteomics identification of ITGB3 as a key regulator in ROS-induced migration and invasion of colorectal cancer cells. Mol. Cell Proteomics, 2011, 10(10), M110.005397. [2] Xie, N.; Huang, K.; Zhang, T.; Huang, K.; Lei, Y.; Wu, H.; Zhao, X.; Nice, E.; Huang, C. Comprehensive proteomic analysis of host cell lipid rafts modified by HBV infection. J. Proteomics, 2012, 75 (3), 725-739. [3] Yuan, K.; Huang, C.; Fox, J.; Gaid, M.; Weaver, A.; Li, G.P.; Singh, B.B.; Gao, H.; Wu, M. Elevated inflammatory response in Caveolin-1 deficient mice with P. aeruginosa infection is mediated by STAT3 and NF-{kappa}B. J. Biol. Chem., 2011, 286(24), 21814-21825. [4] Wang, K.; Liu, R.; Li, J.; Mao, J.; Xie, N.; Wu, J.; Lei, Y.; Zhang, T.; Zeng, J.; Wu, H.; Chen, L.; Huang, C.; Wei, Y. Quercetin induces protective autophagy in gastric cancer cells: Involvement of Akt-mTOR- and hypoxia-induced factor 1α-mediated signaling. Autophagy, 2011, 7(9), 966-978. [5] Hu, H.; Deng, C.; Dong, Q.; Yang, T.; Chen, Y.; Huang, C.; Wei, Y. Proteomics revisits the cancer metabolome. Expert Rev. Proteomics, 2011, 8(4), 505-533. [6] Li, J.; Liu, R.; Lei, Y.; Wang, K.; Lau, Q.C.; Xie, N.; Zhou, S.; Nie, C.; Chen, L.; Wei, Y.; Huang, C. Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells. Autophagy, 2010, 6 (6), 711-724. [7] Liu, R.; Wang, K.; Yuan, K.; Wei, Y.; Huang, C. Integrative oncoproteomics strategies for anti-cancer drug discovery. Expert Rev. Proteomics, 2010, 7(3), 411- 429. [8] Yuan, K.; Lei, Y.; Huang, C. Application of chemistry-based functional proteomics to screening for novel drug targets. Comb. Chem. High Throughput Screen., 13 (5), 414-421. [9] Ren, F.; Wu, H.; Lei, Y.; Zhang, H.; Liu, R.; Zhao, Y.; Chen, X.; Zeng, D.; Tong, A.; Chen, L.; Wei, Y.; Huang, C. Quantitative proteomics identification of phosphoglycerate mutase 1 as a novel therapeutic target in hepatocellular carcinoma. Mol. Cancer, 2010, 9, 81. [10] Liu, R.; Li, Z.; Bai, S.; Zhang, H.; Tang, M.; Lei, Y.; Chen, L.; Liang, S.; Zhao, Y.; Wei, Y.; Huang, C. Mechanism of cancer cell adaptation to metabolic stress: proteomics identification of a novel thyroid hormone mediated gastric carcinogenic signaling pathway. Mol. Cell Proteomics, 2009, 8(1), 70-85. [11] Li, Z.; Zhao, X.; Bai, S.; Wang. Z.; Chen, L.; Wei, Y.; Huang, C. Proteomic identification of cyclophilin A as a potential prognostic factor and therapeutic target in endometrial carcinoma. Mol. Cell Proteomics, 2008, 7(10), 1810-1823. [12] Wang, Z.; Jiang, L.; Huang, C.; Li, Z.; Tong, A.; Chen, L.; Shen, J.; Gao, F.; Chen, Q. Comparative proteomic approach to screening of potential diagnostic and therapeutic targets for oral squamous cell carcinoma. Mol. Cell Proteomics, 2008, 7, 1639-1650. [13] Tong, A.; Gou, L.; Lau, Q.; Li, J.; Zhao, X.; Chen, L.; Tang, H.; Huang, C.; Wei Y. Proteomic Profiling identifies aberrant epigenetic modifications induced by hepatitis B virus X protein. J. Proteome Res., 2009, 8(2), 1037-1046. [14] Tong, A.; Wu, L.; Lin, Q.; Lau, Q.; Li, J.; Chen, L.; Tang, H.; Huang, C.; Wei, Y. Proteomic analysis of cellular protein alterations using a HBV-producing cellular model. Proteomics 2008, 8, 2012-2023. [15] Li, Z.; Huang, C.; Bai, S.; Pan, X.;, Zhou, R.; Wei, Y.; Zhao, X. Prognostic evaluation of epidermal fatty acid-binding protein and calcyphosine, two proteins implicated in endometrial cancer using a proteomic approach. Int. J. Cancer, 2008, 123 (10), 2377-2383. [16] Shen, J.; Huang, C.; Jiang, L.; Gao, F.; Wang, Z.; Zhang, Y.; Bai, J.; Chen, Q. Enhancement of cisplatin induced apoptosis by suberoylanilide hydroxamic acid in human oral squamous cell carcinoma cell lines. Biochem. Pharmacol., 2007, 73(12), 1901-1909. [17] Huang, C.; Ida, H.; Ito, K.; Zhang, H.; Ito, Y. Contribution of reactivated RUNX3 to inhibition of gastric cancer cell growth following suberoylanilide hydroxamic acid (vorinostat) treatment. Biochem. Pharmacol.,2007, 73(7), 990-1000. [18] Tong, A.; Zhang, H.; Li, Z.; Gou, L.; Wang, Z.; Wei, H.; Tang, M.; Liang, S.; Chen, L.; Huang, C.; Wei, Y. Proteomic analysis of liver cancer cells treated with suberonylanilide hydroxamic acid. Cancer Chemother. Pharmacol., 2008, 61(5),791-802. [19] Zhou, S.; Liu, R.; Zhao, X.; Huang, C.; Wei, Y. Viral Proteomics: the emerging cutting edge of virus research. Sci. China Life Sci., 2011, 54(6), 502-512.

Polysaccharide CSPs are recognized widely in chiral chromatography but the introduction of immobilized phases (Chiralpak IA, Chiralpak IB and Chiralpak IC columns) is a remarkable achievement. The immobilized CSPs can be used with organic, normal and reversed phase modes; even with prohibited solvents too (tetrahydrofuran, chlorofom, dichloromethane, acetone, 1,4-dioxane, ethylacetate, and certain other ethers). Their susceptibilities to work with a wide range of solvents have increased the range of applications including chiral recognition mechanisms. Besides, these are also useful for monitoring the progress of stereo-specific reactions; normally need prohibited solvents. The present review describes the various aspects of commercial available immobilized chiral columns. Attempts have been made to discuss immobilized polysaccharides CSPs, immobilized vs coated CSPs, comparison of immobilized CSPs, method development, optimization, chiral recognition mechanism and applications. The chiral recognition capabilities of commercial columns were in the order of Chiralpak IA > Chiralpak IB > Chiralpak IC columns; but complimentary to each other. Of course, these CSPs are not fully developed and need more advancements and applications. Definitely, the future of immobilized CSPs is quite better. Hopefully, in the coming years they will be the choice of the chromatographers for chiral separations in liquid chromatography.

Drug resistance to existing antibiotics poses alarming threats to global public health, which inspires heightened interests in searching for new antibiotics, including antimicrobial peptides (AMPs). Accurate prediction of antibacterial activities of AMPs may expedite novel AMP design and reduce the costs and efforts involved in laboratory screening. In the present study, a novel quantitative prediction method of AMP was established by quantitative structure-activity relationship (QSAR) modeling based on the physicochemical properties of amino acids. The indices of these physicochemical properties were used to define AMP. The structural variables were optimized by stepwise regression (STR). Three series of AMPs from the QSAR model were constructed by multiple linear regressions (MLR). These QSAR models showed good performance in reliability and predictability. The normalized regression coefficients of the QSAR model and the contribution of amino acids at each position of AMP may determine the suitableness of a particular residue at any given position. QSAR models constructed by STR-MLR should prove to be useful tools in peptide design with respect to the calculation, explanation, good and reliable performance, and definition of physiochemical properties.

A one-pot synthesis of cyclopentanone derivatives from phosphorus ylide under lab-type microwave assisted methodology was described. The phosphorus ylides were obtained via the reaction of activated acetylenic compounds, ethyl 4-chloroacetoacetate and triphenylphosphine. The structure of phosphorus ylides was assigned by 1H, 13C and 31PNMR. The phosphorus ylides as precursor were crystallized as two enantiomers (R,R) and (S,S) and one of the phosphorus ylide structures was confirmed by single X-ray crystallography.