Manila 2014 Meeting Report

“Manifesting chemical biology in Manila”
(Asian Chemical Biology Initiative, Manila Meeting)

When it took over governance of the Philippines in 1898 after the Spanish–American War, the United States began Americanizing the former Spanish colony and built the first modern premiere hotel in Manila: the Manila Hotel. This historical hotel has hosted many important guests, and its penthouse once served as the residence of Douglas MacArthur, the famed World War II general. This year we added one more event to the history of the hotel: the 2014 Annual Meeting of the Asian Chemical Biology Initiative (ACBI). Manila was selected as the location of the 2014 meeting because the Philippines is one of Asia’s fastest growing countries where chemical biology is only now emerging.

Like the previous gatherings in Hanoi and Bangkok, the Manila meeting was convened for a day and a half from 25 January to 26 January with the purpose of continuing efforts to promote chemical biology in the region. The first aim is to develop a strong regional chemical biology conference modelled after the Gordon Research Conferences, a well-established conference series. The premise is to hold a closed meeting of principal investigators organized to foster international collaborations, to share research resources, and to streamline chemical biology research in the region. During the conference, 42 ACBI principal investigators gave lectures describing their ongoing research, with the intention of creating opportunities for joint projects. The presentations covered a wide range of topics and are briefly summarized in the latter half of this report.

STUDENT INTERVIEW SESSION

The second goal of the annual conference is to introduce and implement chemical biology in emerging countries in Southeast Asia. Members of the ACBI believe that one of the most effective ways to promote chemical biology is proactive recruitment of the brightest students to the field. Three months before the meeting, Young-Tae Chang (National University of Singapore) and Motonari Uesugi (Kyoto University) presented a week-long ACBI-sponsored class at the University of the Philippines to introduce chemical biology to graduate students and to encourage them to register for an interview at the Manila meeting. Among a total of 63 applications, 36 students were invited to a half-day interview session. The ACBI meeting participants had an opportunity to meet one-on-one with about eight students each and talk with them about research and scholarship opportunities for overseas Ph.D. programs in individual countries or at specific institutions. The interview session was highly productive, largely because the Filipino students are proficient in English and are highly motivated to study abroad for an advanced degree.

SCIENTIFIC SESSIONS

Membrane and membrane proteins
Shiroh Futaki (Kyoto University) reported on the importance of cell membrane curvature, which influences the permeability of octa-arginine peptide [1]. Sun Choi (Ewha Womans University) talked about the allosteric communications of GPCR (G-protein-coupled receptor) by agonists and structure-based design of adenosine receptor modulators [2]. Akihiro Kusumi (Kyoto University) described single-molecule tracking results, which would completely change the conventional view of raft domains in the plasma membrane [3]. Ming-Wei Wang (Shanghai Institute of Materia Medica) reported the results of a crystallographic 3D structural study of human glucagon receptor that is a class BGPCR [4]. Yongseok Choi (Korea University) described research to determine the molecular mechanisms by which the agonists and antagonists of leukotriene B4 receptors BLT1 and BLT2 exhibit their activity and selectivity.

Cancer
Timothy M. Dore (New York University Abu Dhabi) summarized research to create a highly active highly selective inhibitor of Rce1p, a potential molecular target for regulating Ras function [5]. Sunghoon Kim (Seoul National University) announced results elucidating the translation and signaling pathways mediated by lysyl-tRNA synthetase [6]. Kyunglim Lee (Ewha Womans University) described findings that support the relationship between the biological function of translationally controlled tumour protein and certain pathological conditions [7]. Youngjoo Kwon (Ewha Womans University) announced how Ca 2 +-mediated nuclear transfer of calpain is involved in DNA repair by inducing Ku80 cleavage [8]. Yong-Xiang Chen (Tsinghua University) described how modified Rheb and Ras were used in a functional analysis of post-translationally modified GTP-binding protein [9]. Peter Shepherd (University of Auckland) talked about a selective inhibitor of p110 α, a PI3K (phosphoinositide 3-kinase) isoform, and its anticancer activity. Junko Ohkanda (Kyoto University) described the structure-based design of cell-permeable inhibitors of protein interactions using a K-Ras prenylation inhibitor as an example [10].

New technology
Kenji Monde (Hokkaido University) introduced how he and his colleagues have used IR vibrational circular dichroism spectrometry to analyze the chirality of biomolecule-related compounds. Zhen Xi (Nankai University) introduced a quantitative structure–activity relationship study based on a protein for drug-resistance mutation [11]. Seung Bum Park (Seoul National University) introduced a target identification method based on differences in fluorescence observed with 2D gel electrophoresis (FITGE) and described his rational drug-discovery research using FITGE-based phenotype screening. Yan-Mei Li (Tsinghua University) discussed the process of protein misfolding and described how to design its inhibitors using a tau protein degradation promoter as an example.

Imaging
Dan Ohtan Wang (Kyoto University) summarized her study designed to elucidate the mechanism of memory by using an RNA fluorescence probe to label particular RNAs in mouse brain sections [12]. Young-Tae Chang (National University of Singapore) presented DOFLA (Diversity-Oriented Fluorescence Library Approach) as a universal method for sensor and probe generation against a broad range of biomolecules and live cells [13]. Motonari Uesugi (Kyoto University) announced how his group used a FRET-based molecular design to develop a small-molecule probe for visualizing mRNA in living cells and introduced the applications of the technique. Takeaki Ozawa (University of Tokyo) presented a newly developed technique for Akt photocontrol and discussed the results of an analysis using a mathematical model. Kazuya Kikuchi (Osaka University) described the molecular design, synthesis and biological application of a highly sensitive nanoparticle-type 19 F MRI probe [14]. Mikiko Sodeoka (RIKEN) summarized a new method that uses Raman microscopy to image alkyne tags that, in turn, are used to visualize small molecules in living cells [15]. Hideko Nagasawa (Gifu Pharmaceutical University) talked about the creation and application of an Fe(II) ion turn-on-type fluorescence probe and the development of a new drug-delivery system based on the lipopeptide pepducin [16]. Yoshie Harada (Kyoto University) talked about characterization of the process of hemi-methylated DNA recognition by the SRA (SET and RING-associated) domain of methylated CpG-binding protein using a new single-molecule imaging technique known as zero-mode waveguides [17].

Enzymes
Hea-Young Park Choo (Ewha Womans University) summarized a study aimed at creating a 5-lipoxygenase inhibitor to be used to develop an anti-inflammatory drug [18]. Takayoshi Suzuki (Kyoto Prefectural University of Medicine) explained the chemical control of epigenetics using a lysine-specific demethylase 1-selective inhibitor as an example [19]. Minoru Yoshida (RIKEN) reported novel inhibitors of SUMOylation and deSUMOylation, which were discovered by unique screening systems using a natural products-based compound library; the featured inhibitors are small-molecule compounds that inhibit SUMO E2 enzyme, SUMO-specific protease 1 and SUMO–SIM interactions [20].

Nucleic acids
Kazuhiko Nakatani (Osaka University) discussed a small-molecule organic compound that controls RNA structure and function [21]. Fumi Nagatsugi (Tohoku University) showed that aminovinylpurine conjugated with acridine exhibited high-selective chemical modification in the opposite site of an abasic site in the duplex DNA [22]. Takashi Morii (Kyoto University) described a technique for arranging two enzymes on a DNA origami to facilitate two-step reactions [23]. Hiroshi Sugiyama (Kyoto University) talked about how highly efficient gene expression and induction of cells, such as induced pluripotent stem cells, can be achieved using a hybrid molecule that consists of the histone deacetylase inhibitor SAHA (suberanilohydroxamic acid) and a pyrrole-imidazole polyamide that specifically recognizes DNA sequences [24].

Natural products
Midori Arai (Chiba University) summarized a study investigating naturally occurring and synthetic modulators of the neural stem-cell bHLH transcription factors [25]. Yoichi Nakao (Waseda Uni-versity) described an exploratory study intended to identify marine natural products with novel chemical skeletons; he described how he isolated a novel compound with a phenanthrene nucleus from a bycatch mixture of marine organisms and determined the structure and bioactivity of the compound [26]. Jianhua Qi (Zhejiang University) discussed the bioactivity of hormone α 1, which induces the sexual reproduction of Phytophthora, a causal micro-organism involved in plant diseases [27].

Target identification
Ho Jeong Kwon (Yonsei University) explained how he used multiomics analysis for target identification and validation of terpestacin and an autophagy-promoting compound [28]. Gyoonhee Han (Yonsei University) described his study of target identification of known small-molecule compounds based on their structural homology using an FLT3 receptor inhibitor as an example. Hiroyuki Osada (RIKEN) summarized a technique for identifying target molecules based on compound-induced proteomic changes using pyrrolizilactone as an example [29]. Yan Zhang (Nanjing University) discussed the discovery and target identification of small-molecule compounds that activate or suppress the function of miRNA [30].

Session dedicated to research in the Philippines
Three researchers from universities in the Philippines presented results of their chemical biology studies. Gisela P. Concepcion (University of the Philippines Diliman) explained the biodiversity of marine organisms in the Philippines and summarized her drug discovery research based on naturally occurring products derived from such organisms [31]. Salvador Eugenio C. Caoili (University of the Philippines Manila) talked about using B-cell epitope prediction for biomedical applications such as developing peptide-based vaccines [32]. Nina Rosario L. Rojas (Ateneo de Manila University) discussed an exploratory study aimed at discovery of plant-derived natural compounds that possess biological tissue-regeneration activity.

Special session
Florante A. Quiocho, a Philippines-born Professor from Baylor College of Medicine in the U.S.A., who made the Manila meeting possible, concluded the scientific session. His special lecture focused on an analysis of the 3D structure of cancer-associated FAS (fatty acid synthase) and on his quest to discover a novel FAS inhibitor by using structure-based drug design.

Conclusion
Conference participants engaged in lively discussions throughout the meeting, during the scientific and student interview sessions, and at social events. The outdoor banquet dinner overlooking Manila Bay at sunset was attended by Lourdes Cruz, the President of the National Research Council of the Philippines. Her attendance indicated the high expectations for chemical biology in the country. Daily Asian newspapers have reported record levels of economic growth in the Philippines in recent years. The English-speaking population of the country is nearly 100 million, the largest number in Asia. However, most attendees had never had the chance to visit the Philippines before. The meeting provided an opportunity for us to envision the bright future of the country and to experience its excitement by walking traffic-jammed city streets and having face-to-face contacts with highly motivated young faculty members and students who are enthusiastic about the future of chemical biology. We left Manila with exuberance and our dried mango souvenirs. We were leaving as General McArthur had in 1942, and in his historical speech, he said three words that still resound today, “I shall return.” We know we, too, shall return.

ACKNOWLEDGMENTS
The meeting received support from the Biochemical Journal and Chemistry & Biology, the Royal Society of Chemistry, the Asian CORE Program of the Japan Society for the Promotion of Science, and the Maurice Wilkins Centre for Molecular Biodiscovery.

REFERENCES

  1. Pujals, S., Miyamae, H., Afonin, S., Murayama, T., Hirose, H., Nakase, I., Taniuchi, K., Umeda, M., Sakamoto, K., Ulrich, A. S. and Futaki, S. (2013) Curvature engineering: positive membrane curvature induced by epsin N-terminal peptide boosts internalization of octaarginine. ACS Chem. Biol. 8, 1894–1899
  2. Lee, Y., Choi, S. and Hyeon, C. (2014) Mapping the intramolecular signal transduction of G-protein coupled receptors. Proteins 82, 727–743
  3. Suzuki, K. G., Kasai, R. S., Hirosawa, K. M., Nemoto, Y. L., Ishibashi, M., Miwa, Y., Fujiwara, T. K. and Kusumi, A. (2012) Transient GPI-anchored protein homodimers are units for raft organization and function. Nat. Chem. Biol. 8, 774–783
  4. Siu, F. Y., He, M., de Graaf, C., Han, G. W., Yang, D., Zhang, Z., Zhou, C., Xu, Q., Wacker, D., Joseph, J. S. et al. (2013) Structure of the human glucagon class B G-protein-coupled receptor. Nature 499, 444–449
  5. Dore, T. M. and Schmidt, W. K. (2013) Isoprenylated protein peptidase Rce1p. In Handbook of Proteolytic Enzymes Vol. 2, 3rd edition (Rawlings, N. D. and Salvesen, G. S., eds), pp. 1720–1726, Elsevier, Oxford
  6. Kim, D. G., Lee, J. Y., Kwon, N. H., Fang, P., Zhang, Q., Wang, J., Young, N. L., Guo, M., Cho, H. Y., Mushtaq, A. U. et al. (2013) Chemical inhibition of prometastatic lysyl-tRNA synthetase-laminin receptor interaction. Nat. Chem. Biol. 10, 29–34
  7. Kim, M., Kim, M., Kim, H. Y., Kim, S., Jung, J., Maeng, J., Chang, J. and Lee, K. (2011) A protein transduction domain located at the NH2-terminus of human translationally controlled tumor protein for delivery of active molecules to cells. Biomaterials 32, 222–230
  8. Chou, S. M., Huang, T. H., Chen, H. C. and Li, T. K. (2011) Calcium-induced cleavage of DNA topoisomerase I involves the cytoplasmic-nuclear shuttling of calpain 2. Cell. Mol. Life Sci. 68, 2769–2784
  9. Ismail, S. A., Chen, Y.-X., Rusinova, A., Chandra, A., Bierbaum, M., Gremer, L., Triola, G., Waldmann, H., Bastiaens, P. I. H. and Wittinghofer, A. (2011) Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo. Nat. Chem. Biol. 7, 942–949
  10. Machida, S., Kato, N., Harada, K. and Ohkanda, J. (2011) Bivalent inhibitors for disrupting protein surface-substrate interactions and for dual inhibition of protein prenyltransferases. J. Am. Chem. Soc. 133, 958–963
  11. He, Y., Niu, C., Wen, X. and Xi, Z. (2013) Biomacromolecular 3D-QSAR to decipher molecular herbicide resistance in acetohydroxyacid synthases. Mol. Inform. 32,139–144
  12. Wang, D. O., Matsuno, H., Ikeda, S., Yanagisawa, H., Hayashi, Y. and Okamoto, A. (2012) A quick and simple FISH protocol with hybridization-sensitive fluorescent linear oligodeoxynucleotide probes. RNA 18, 166–175
  13. Kang, N. Y., Ha, H. H., Yun, S. W., Yu, Y. H. and Chang, Y. T. (2011) Diversity-driven chemical probe development for biomolecules: beyond hypothesis-driven approach. Chem. Soc. Rev. 40, 3613–3626
  14. Matsushita, H., Mizukami, S., Sugihara, F., Nakanishi, Y., Yoshioka, Y. and Kikuchi, K. (2014) Multifunctional core-shell silica nanoparticles for highly sensitive 19 F MRI. Angew. Chem. Int. Ed. 53, 1008–1011
  15. Yamakoshi, H., Dodo, K., Palonpon, A., Ando, J., Fujita, K., Kawata, S. and Sodeoka, M. (2012) Alkyne-tag Raman imaging for visualization of mobile small molecules in live cells. J. Am. Chem. Soc. 134, 20681–20689
  16. Hirayama, T., Okuda, K. and Nagasawa, H. (2013) A highly selective turn-on fluorescent probe for iron(II) to visualize labile iron in living cells. Chem. Sci. 4,1250–1256
  17. Han, Y.-W., Tsunaka, Y., Yokota, H., Matsumoto, T., Kashiwazaki, G., Morinaga, H., Hashiya, K., Bando, T., Sugiyama, H. and Harada, Y. (2014) Construction and characterization of Cy3- or Cy5-conjugated hairpin pyrrole/imidazole polyamides binding to DNA in the nucleosome. Biomater. Sci. 2, 297–307
  18. Lee, J. M., Park, H., Noh, A. L., Kang, J. H., Chen, L., Zheng, T., Lee, J., Ji, S. Y., Jang, C. Y., Shin, C. S. et al. (2012) 5-Lipoxygenase mediates RANKL-induced osteoclast formation via the cysteinyl leukotriene receptor1. J. Immunol. 189, 5284–5292
  19. Ogasawara, D., Itoh, Y., Tsumoto, H., Kakizawa, T., Mino, K., Fukuhara, K., Nakagawa, H., Hasegawa, M., Sasaki, R., Mizukami, T. et al. (2013) Lysine-specific demethylase 1-selective inactivators: protein-targeted drug delivery mechanism. Angew. Chem. Int. Ed. 52, 8620–8624
  20. Hirohama, M., Kumar, A., Fukuda, I., Matsuoka, S., Igarashi, Y., Saitoh, H., Takagi, M., Shin-Ya, K., Honda, K., Kondoh, Y. et al. (2013) Spectomycin B1 as a novel SUMOylation inhibitor that directly binds to SUMO E2. ACS Chem. Biol. 8, 2635–2642
  21. Hong, C., Otabe, T., Matsumoto, S., Dohno, C., Murata, A., Hagihara, M. and Nakatani, K. (2014) Formation of a ligand-assisted complex of two RNA hairpin loops. Chemistry 20,5282–5287
  22. Hagihara, S., Lin, W. C., Kusano, S., Chao, X. G., Hori, T., Imoto, S. and Nagatsugi, F. (2013) The crosslink formation of 2 ‘-OMe oligonucleotide containing 2-amino-6-vinylpurine protects mRNA from miRNA-mediated silencing. ChemBioChem 14, 1427–1429
  23. Ngo, T. A., Nakata, E., Saimura, M., Kodaki, T. and Morii, T. (2014) A protein adaptor to locate a functional protein dimer on molecular switchboard. Methods 67,142–150
  24. Pandian, G. N., Taniguchi, J., Junetha, S., Sato, S., Han, L., Saha, A., Anandhkumar, C., Bando, T., Nagase, H., Thangavel, V., Taylor, R. D. and Sugiyama, H. (2014) Distinct DNA-based epigenetic switches trigger transcriptional activation of silent genes in human dermal fibroblasts. Sci. Rep. 4, 3843
  25. Arai, M. A., Koryudzu, K., Koyano, T., Kowithayakorn, T. and Ishibashi, M. (2013) Naturally occurring Ngn2 promoter activators from Butea superba. Mol. BioSyst. 9,2489–2497
  26. Machida, K., Abe, T., Okamoto, M., Shimizu, I., de Voogd, N. J., Fusetani, N. and Nakao, Y. (2014) Cinanthrenol A, an estrogenic steroid containing phenanthrene nucleus, from a marine sponge Cinachyrella sp. Org. Lett. 16, 1539–1541
  27. Qi, J., Asano, T., Jinno, M., Matsui, K., Atsumi, K., Sakagami, Y. and Ojika, M. (2005) Characterization of a Phytophthora mating hormone. Science 309,1828
  28. Cho, Y. S. and Kwon, H. J. (2012) Identification and validation of bioactive small molecule target through phenotypic screening. Bioorg. Med. Chem. 20,1922–1928
  29. Futamura, Y., Kawatani, M., Muroi, M., Aono, H., Nogawa, T. and Osada, H. (2013) Identification of a molecular target of a novel fungal metabolite, pyrrolizilactone, by phenotypic profiling systems. ChemBioChem 14, 2456–2463
  30. Li, J., Tan, S., Kooger, R., Zhang, C. and Zhang, Y. (2014) MicroRNAs as novel biological targets for detection and regulation. Chem. Soc. Rev. 43,506–517
  31. Cabang, A. B., Imperial, J. S., Gajewiak, J., Watkins, M., Corneli, P. S., Olivera, B. M. and Concepcion, G. P (2011) Characterization of a venom peptide from a crassispirid gastropod. Toxicon 58, 672–680
  32. Caoili, S. E. (2012) On the meaning of affinity limits in B-cell epitope prediction for antipeptide antibody-mediated immunity. Adv. Bioinformatics. 2012, 346765