FOLDING CYSTEINE-RICH MINIPROTEINS

Transcription

1 Second International Collaborative and Cooperative Chemistry Symposium Program: Tuesday 1 November Lecture Theatre 358; 1.15 pm 2.45 pm FLDING CYSTEINE-RICH MINIPRTEINS Professor Paul Alewood University of Queensland Many organisms including snakes, spiders, scorpions, cone snails, fish and some mammalian species have evolved venom as either a defence mechanism or a weapon for prey capture 1. These venoms typically contain a complex cocktail of bioactive disulfide-rich small polypeptides which target a wide range of receptors including ion channels, GPCRs, transporters and enzymes. f interest to drug designers is their high potency combined with their resistance to many proteases. f particular interest are venoms from the Conidae, with smaller polypeptide chains of amino acids that are highly constrained by two to four disulfide bridges and structurally welldefined. Their high potency and exquisite selectivity for ion channels and receptors has led to two drug candidates 2,3 from our laboratories. In this presentation I will outline the use of selenocysteine in a supported phase method to direct native folding and produce conotoxins with improved biophysical properties. By replacing complementary cysteine pairs with selenocysteine pairs on an amphiphilic resin, we were able to chemically direct all five structural subclasses of a-conotoxins exclusively to their native folds with similar or improved potency plus exceptional stability in plasma. Together, these results underpin the development of more stable and potent nicotinic antagonists suitable for new drug therapies, and highlight the application of this technology more broadly to disulfide-bonded peptides and proteins. 1. Myers R, Cruz L, Rivier J and livera, BM (1993). Chem Rev 93, RL Lewis, D Adams, I.Sharpe, M Loughnan, T Bond, L Thomas, A. Jones, J Matheson, R Drinkwater, K Nielsen, DJ Craik and PF Alewood (2000). J Biol Chem, 275(45) I Sharpe, J Gehrmann, M Loughnan, L Thomas, D Adams A Atkins, DJ Craik, D Adams PF Alewood and RJ Lewis (2001). Nature Neuroscience, 4(9)

2 Professor Paul Alewood Second International Collaborative and Cooperative Chemistry Symposium University of Queensland Paul Alewood is Professor and former Head of the Division of Chemical and Structural Biology at the Institute for Molecular Bioscience (IMB) at the University of Queensland, Australia. He established the successful toxins program at the former Centre for Drug Design and Development (now the IMB) in 1990 and has championed molecular research on toxins from Australia s venomous creatures. He has codiscovered several bioactive peptides which are undergoing either preclinical (TNPc) or clinical trials (CNSB004, Xen 2174). He was a founder of Xenome whose prime goal is to develop the toxin lead molecules emerging from Australian biodiversity. He is the co-founder of the Australian Peptide Symposia and the Venoms to Drugs Symposia held on Heron Island. Professor Alewood is the author of over 240 publications in high quality journals. He is an inventor on 11 licensed patents. He is on several journal editorial boards and a referee for many major journals involved in peptide chemistry, biochemistry and medicinal chemistry. He is a consultant to the biotechnology industry and on several scientific advisory boards. He is a regular speaker at national and international forums and his research interests focus on the discovery and synthesis of bioactive peptides, the chemical synthesis of proteins, and the design of peptidomimetics. 69

3 Second International Collaborative and Cooperative Chemistry Symposium Program: Tuesday 1 November Lecture Theatre 358; 1.15 pm 2.45 pm FRM STRUCTURE BASED T SYSTEMS BASED DRUG DESIGN Professor Luhua Lai Peking University Structural based drug design has been widely used in drug discovery for lead compounds identification and optimization. Many successful applications have been reported. Various docking methods and de novo structural based drug design programs have been developed, which were all developed based on the single target binding assumption. However, drugs encounter complicated situations and a huge number of biological molecules in the human body and may cause unexpected deleterious or beneficial effects. In order to understand the mechanism of drug action, disease related molecular networks need to be studied. My group has been working on structure based drug methodologies and their applications 1. Recently, we have extended our study to systems based drug design. We have developed a Multi-Target ptimum Intervention (MTI) method for key target identification and optimum intervention strategy discovery to shift a biological network from a disease state to a normal state 2. As systems-based drug intervention often requires simultaneous control of multiple targets, we also explored possible ways for multi-target based drug design 3,4. MTI has been successfully used in simulating the inflammation related arachidonic acid metabolic network and in predicting novel combinatorial control solutions. As cancers are typical complex diseases that are too robust to treat, analysis of the underlying molecular networks may provide possible solutions for anti-cancer therapy. We have studied various cancer related networks and insights for cancer therapy will be discussed. 1. Yuan, YX, Pei, JF, Lai, LH, LigBuilder 2: A Practical de Novo Drug Design Approach. J Chem Inf Model 2011, 51, Yang, K, Bai, HJ, Lai, LH, et al. Finding multiple target optimal intervention in diseaserelated molecular network. Mol Syst Biol 2008, 4, Wei, DG, Jiang, XL, Lai, LH, et al. Discovery of Multitarget Inhibitors by Combining Molecular Docking with Common Pharmacophore Matching. J Med Chem 2008, 51, Chen, Z, Liu, Y, Lai, LH, et al. Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A(4) Hydrolyase. J. Med. Chem. 2011, 54,

4 Professor Luhua Lai Second International Collaborative and Cooperative Chemistry Symposium Peking University Luhua Lai got her BS and PhD in the Department of Chemistry, Peking University in 1984 and She then joined the faculty of the same department as lecturer, and became a full professor in During , she was a Berkeley Scholar in the University of California at Berkeley. Currently she is Vice Dean and Changjiang Professor in the College of Chemistry and Molecular Engineering, Peking University. She is also a member of the Center for Theoretical Biology, Peking University. Luhua Lai serves as associated editor for PLoS Computational Biology and editorial board member for BMC Bioinformatics. 71

5 Second International Collaborative and Cooperative Chemistry Symposium Program: Tuesday 1 November Lecture Theatre 358; 1.15 pm 2.45 pm PLYENYLPYRRLE DERIVATIVES: ANTICANCER AGENTS ACTING THRUGH CASPASES-DEPENDENT APPTSIS Professor Yulin Lam National University of Singapore Cancer, being one of the leading causes of death globally, is a disease of worldwide importance. Although anticancer drugs have played a major role in the success stories in cancer treatment, there are still many types of cancers where effective molecular therapeutics are nonexistent. Hence, there is an impetus to identify and develop more potent therapeutic agents for cancer. Conjugated polyenes are an interesting class of widely occurring natural products, as they have been shown to possess excellent biological properties. Thus far, the main source for these compounds has been from the isolation of fungi or bacteria. They typically small quantities that can be obtained via these sources often limit the extent of biological work that can be carried out. To address this limitation as well as to provide access to structurally diverse analogues of these compounds, we have designed and synthesized a class of polyenylpyrroles and evaluated the compounds for their cell cytotoxicity against human nonsmall-cell lung carcinoma cell line A549. Two compounds (Figure 1) were found to exhibit high cytotoxicity against A549. These two compounds were nontoxic to normal human lung Beas-2b cells, indicating that they are highly selective in their cytotoxicity activities. Furthermore, on compound showed in vivo anticancer activity in human-lung-cancer-cellbearing mice. Acknowledgment: The author thanks the Ministry of Education (MoE (Tier 2)) for funding support. CH 3 CH 3 H N H N Cl Auxarconjugatin B, IC 50 =0.6 M 1g, IC 50 =0.01 M Cl 72

6 Professor Yulin Lam Second International Collaborative and Cooperative Chemistry Symposium National University of Singapore Yulin Lam received her B.Sc.(Hons) in chemistry from the National University of Singapore and obtained her Ph.D. from the same institution in Thereafter she proceeded to the Scripps Research Institute where she worked on catalytic antibodies under Professor Kim D. Janda. In 1994, she returned to Singapore and joined the Institute of Molecular and Cell Biology. She joined the Department of Chemistry, National University of Singapore, in Her research institute covers bioorganic and medicinal chemistry and the development of environmentally friendlier synthetic methodologies. 73