Drug Discovery Whitepaper

Drug Discovery Submitters Jean Chmielewski (CHM) David Sanders (BIO) Timothy Zwier (CHM) Richard Kuhn (BIO) 1. Multidisciplinary Research Area Launch a multidisciplinary hiring effort in Drug Discovery that promotes research strengths in (1) identifying disease-relevant biomolecular targets, (2) elucidating the structure of these targets and target-drug complexes by x-ray crystallography and NMR spectroscopy, and (3) identifying agents with activity against these disease-relevant targets through design and screening efforts. Specifically this hiring effort will seek to bring strengths in drug-resistant targets (DR), emerging pathogens (EP), neurodegenerative disease (ND) and oncology (O) to the College of Science and the University. Hiring partnerships with Medicinal Chemistry, Biomedical Engineering, Veterinary Medicine and Biochemistry will be initiated. This hiring initiative seeks to put Purdue University at the forefront of Drug Discovery research. 2. Scientific Merit and Potential for Societal Impact In spite of the availability of effective drugs to treat many human diseases, there is currently a profound need for new therapeutics against some of the greatest threats to human health in the 21st century. For instance the emergence of resistance to many known therapeutics, including antibiotics, antiparasitics, antivirals and anticancer therapies, is a huge challenge to the biomedical community. Likewise disease due to emerging pathogens, such as avian flu, west nile virus, ebola, and anthrax, pose a profound risk, and their threat to human health as agents of bioterrorism cannot be overstated. In addition, advances in our understanding of the molecular basis of neurodegenerative diseases and cancer have enhanced the potential for target-based pharmaceutical interventions 3. Potential for Funding Since drug resistance, emerging pathogens, neurodegenerative disease and cancer are recognized as global threats to health, there is great potential to attract significant external funding for research in Drug Discovery. Strategic hires in the area of Drug Discovery will be made to foster funding initiatives through center proposals, project grant proposals, and multiinvesttigato grant proposal. A partial list, for instance, of requests for proposals from the National Institutes of Health in the areas of Drug Discovery outlined in this white paper is found below. Many other governmental and private sources would also be explored. • Drug Discovery for Nervous System Disorders • Solicitation of Assays for High Throughput Screening in the Molecular Libraries Screening Centers Network • Alzheimer's Disease Drug Development Program • Centers for AIDS Research • Morris K. Udall Parkinson’s Disease Centers of Excellence • NINDS Institutional Center Core Grants to Support Neuroscience Research • Novel Approaches To Study Polymicrobial Diseases • HIV Infection Of The Central Nervous System • Biodefense and Emerging Infections Disease Research Opportunities • Cooperative Research Partnerships for Biodefense • Non-Biodefense Emerging Infectious Diseases Research Opportunities • Antimicrobial Resistance 4. Current Purdue Faculty and Research Interests Current DD Researchers in COS Current DD Researchers outside COS (1) Identify disease-relevant protein targets Erik Barton (BIO, DR) Richard Borgens (BME/VM; ND) Peter Hollenbeck (BIO, ND) Doug LaCount (MCMP; DR) Christine Hrycyna (CHM; DR, O, ND) Xaoqi Liu (BCHM, O) Richard Kuhn (BIO; DR, EP) Tsang Long Lin (VP, EP) Phil Low (CHM; EP, O) Susan Mendrysa (BMS, O) Zhao-Qing Luo (BIO; EP) Chris Rochet (MCMP; ND) David Sanders (BIO; EP) Val Watts (MCMP, ND) Kavita Shah (CHM; O, ND) Daoguo Zhou (BIO; DR) (2) Elucidate the structure of disease-relevant targets Jue Chen (Bio; EP) Barb Golden (BCHM/BIO; DR) Richard Kuhn (BIO; EP, DR) Carol Post (BIO/MCMP; DR, O) Michael Rossmann (BIO; EP, DR) Cynthia Stauffacher (BIO; DR, O) Dinesh Yernool (BIO; ND) (3) Identify agents with activity against disease-relevant targets Jean Chmielewski (CHM; DR, EP, O, ND) Richard Borch (MCMP; O) Phil Fuchs (CHM; DR, O) Mark Cushman (MCMP; DR, EP, O) Arun Ghosh (CHM/MCMP; DR, O, ND) Richard Gibbs (MCMP; O) Mark Lipton (CHM; DR, O, ND) Dave Nichols (MCMP; ND) Sergey Savinov (CHM; DR, O, ND) The area of Drug Discovery is very attractive to graduate students, and an outstanding pool of potential faculty candidates exists in all three areas 5. Synergy with Departments, Schools, Colleges and Discovery Park Departmental Participants Core groups of scientists across campus currently work in the area of Drug Discovery. The aim of this hiring initiative is to improve the synergy between these different groups by bringing key individuals to campus to serve as bridges between scientific disciplines, departments, schools and centers. College of Science Department of Biology Department of Chemistry Outside the College of Science Department of Medicinal Chemistry and Molecular Pharmaceutics Department of Biomedical Engineering Department of Biochemistry Department of Veterinary Medicine Interactions with Campus Centers Many opportunities exist for a Drug Discovery hiring effort to synergize with Centers within Discovery Park and across campus including: • Bindley Biosciences Center • Birck Nanotechnology Center • Oncological Sciences Center • Purdue Cancer Center 6. Grant Support in the Area of Drug Discovery for COS Researchers Jue Chen Current: • NIH, Studies of flavivirus and alphavirus membrane proteins Jean Chmielewski Current: • NIH, Cancer Targeting with Multi-Responsive Core/Shell Microgels • Showalter Trust, Blocking Anthrax Toxin Interactions with Designed Agents Pending: • NIH, Development of Small Molecule Anthrax Anti-Toxins • NIH, Modulating P-glycoprotein to Enhance Neurodegenerative Drug Penetration of Brain Phil Fuchs Current: • NIH, Synthesis of Cephalostatin Anticancer Drugs • BiogenIdec, Inc. Boston, Synthesis of Cephalostatin-Antibody Conjugates Pending: • NIH, Modeling & Synthesis of Neuraminidase Inhibitors for Viral Detection & Treatment Arun Ghosh Current: • NIH “Design and Synthesis of Nonpeptide HIV Protease Inhibitors” • NIH “For Treating Alzheimer’s Disease” • NIH “Design and Synthesis of SARS-3CLpro Inhibitors for SARS” Christine Hrycyna Current: • NIH, Inhibition of Prenylated Protein Processing • NIH, Development of an Icmt Supported Membrane Sensor Pending: • NIH, Modulating P-glycoprotein to Enhance Neurodegenerative Drug Penetration of Brain Richard Kuhn Current: • NIH, Molecular Basis of Alphavirus Assembly • NIH, Virus Assembly and Transmission • NIH, Development of antiviral strategies for enveloped viruses • PDVI, Role of antibodies in controlling Dengue virus infection • NIH, Structure-Function Studies of alpha-and Flaviviruses • Showalter Trust, Identification of human protein binding partners of Dengue virus proteins Mark Lipton Current: • Showalter Trust, Blocking Anthrax Toxin Interactions with Designed Agents Pending: • NIH, Development of Small Molecule Anthrax Anti-Toxins • NIH, Structure-Function Studies of Bioactive Cyclic Depsipeptides • NIH, Design and Synthesis of Resveratrol Analogues as Therapeutics for Age-Related Diseases Philip Low • Endocyte, Inc., Characterization of Folate Receptor-Mediated Endocytosis • Eli Lilly & Co., Characterization of Imaging Techniques to Study the Role of the Folate Receptors in the Uptake of Alimta by Tumor and Normal Tissues • Federal Aviation Administration, Development of methods for pathogen detection Zhao-Qing Luo Current: • American Heart Association, Funtional study ofSidJ, a Legionella pneumophile effector important for intracellular multiplication • NIH, Modulation of host apoptotic pathways by Legionella pneumophila Pending: • NIH, An in vivo gene deletion system for analyzing temporal requirment of the Dot/Icm transporter by Legionella pneumophila Carol Post Current: • NIH, Antiviral activity and disassembly in human rhinovirus • NIH, NMR Structure of peptide-protein complexes • NIH, CAREER: Structure of phosphotyrrosy protein complexes by NMR Michael Rossmann Current: • NSF, X-ray determination of proteins and viruses • NIH, Structure of a small spherical virus • NIH, Parvovirus structure, assembly and receptors • NIH; Virus assembly and transmission • Human Frontiers of Science, Structural genomics of bacteriophage T4: implication to virus assembly and infectivity • NIH, Development of antiviral strategies for enveloped viruses • NIH, Structure of a simple RNA enveloped virus • NIH, Flavivirus structure, assembly, and cell entry • NIH, Structural genomics of bacteriophage ø29 David Sanders Current: • ACS, Mechanism and Regulation of Leukemia Virus Entry into Cells Sergey Savinov Current: • AGEP, Directed Evolution of Site-Specific Proteases for Turnover-Based Selective Therapeutic Inactivation of Angiogenic MMP-2, and -9 Pending: • NIH, Targeting A-beta with evolved site-specific proteases • Faculty Development Incentive Grants, Protecting antiretroviral activity of APOBEC3G from HIV-1 Vif-promoted degradation Kavita Shah Current: • PHS-NIH National Cancer Institute (through Purdue Cancer Center), Role of Aurora Kinase A in Cancer • American Cancer Society (through Purdue Cancer Center), Role of Aurora Kinases in Ovarian Cancer • Purdue Research Foundation, Role of Rab25 G Protein in Ovarian Cancer Pending: • MDA Grant Foundation, Role of CDK5 kinase in Amyotrophic Lateral Sclerosis • Alzheimer Disease Foundation, Role of CDK5 kinase in Alzheimer Disease • NIH, Chemical Genetics of Plasmodium Kinases Cynthia Stauffacher Current: • NSF, Exploring the Mechanism of HMB-CoA Reductase with Time-Resolved Laue Diffraction/NTP Daoguo Zhou Current: • NIH, Modulation of actin-cytoskeleton by Salmonella • NIAID, Role of E3 Ubiquitin ligase in Salmonella-induced inflammation Pending: • AHA, Exploitation of host ubiquitination pathways by Salmonella • NIH, Host cell actin-cytoskeleton rearrangements by Salmonella