Nobel Lecture by Thomas A. Steitz
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Oxazolidinones for TB
Oxazolidinones for TB: Current Status and Future Prospects 12th International Workshop on Clinical Pharmacology of Tuberculosis Drugs London, UK 10 September 2019 Lawrence Geiter, PhD Disclosures • Currently contract consultant with LegoChem Biosciences, Inc., Daejeon, Korea (LCB01-0371/delpazolid) • Previously employed with Otsuka Pharmaceutical Development and Commercialization, Inc. (delamanid, OPC-167832, LAM assay) What are Oxazolidinones • A family of antimicrobials mostly targeting an early step in protein synthesis • Cycloserine technically oxazolidinone but 2-oxazolidinone different MOA and chemical properties • New generation oxazolidinones bind to both 50S subunit and 30S subunit • Linezolid (Zyvox) and Tedizolid (Sivestro) approved for drug resistant skin infections and community acquired pneumonia Cycloserine • Activity against TB demonstrated in non- clinical and clinical studies • Mitochondrial toxicity >21 days limits use in TB treatment Linezolid Developing Oxazolidinones for TB Compound Generic Brand Sponsor Development Status TB Code- Activity/Trials PNU-100766 Linezolid Zyvox Pfizer Multiple regimen Yes/Yes TR-201 Tedizolid Sivextro Merck Pre-clinical efficacy Yes/No PNU-100480 Sutezolid Pfizer Multiple regimen studies Sequella Yes/Yes (PanACEA) TB Alliance LCB01-0371 Delpazolid LegoChem Bio EBA trial recruitment completed Yes/Yes TBI-223 - Global Alliance SAD trial launched Yes/Yes AZD5847 Posizolid AstraZenica Completed EBA Yes/No RX-1741 Radezolid Melinta IND for vaginal infections ?/No RBX-7644 Ranbezolid Rabbaxy None found ?/No MRX-4/MRX-1 Contezolid MicuRx Skin infections Yes/No U-100592 Eperezolid ? No clinical trials ?/No PK of Oxazolidinones in Development for TB Steady State PK Parameters Parameter Linezolid 600 Delpazolid 800 mg QD2 mg QD3 Cmax (mg/L) 17.8 8.9 Cmin (mg/L) 2.43 0.1 Tmax (h) 0.87 0.5 T1/2 (h) 3.54 1.7 AUC0-24 (µg*h/mL) 84.5 20.1 1 MIC90 (µg/mL) 0.25 0.5 References 1. -
Infectious Diseases
2013 MEDICINES IN DEVELOPMENT REPORT Infectious Diseases A Report on Diseases Caused by Bacteria, Viruses, Fungi and Parasites PRESENTED BY AMERICA’S BIOPHARMACEUTICAL RESEARCH COMPANIES Biopharmaceutical Research Evolves Against Infectious Diseases with Nearly 400 Medicines and Vaccines in Testing Throughout history, infectious diseases hepatitis C that inhibits the enzyme have taken a devastating toll on the lives essential for viral replication. and well-being of people around the • An anti-malarial drug that has shown Medicines in Development world. Caused when pathogens such activity against Plasmodium falci- For Infectious Diseases as bacteria or viruses enter a body and parum malaria which is resistant to multiply, infectious diseases were the current treatments. Application leading cause of death in the United Submitted States until the 1920s. Today, vaccines • A potential new antibiotic to treat methicillin-resistant Staphylococcus Phase III and infectious disease treatments have proven to be effective treatments in aureus (MRSA). Phase II many cases, but infectious diseases still • A novel treatment that works by Phase I pose a very serious threat to patients. blocking the ability of the smallpox Recently, some infectious pathogens, virus to spread to other cells, thus 226 such as pseudomonas bacteria, have preventing it from causing disease. become resistant to available treatments. Infectious diseases may never be fully Diseases once considered conquered, eradicated. However, new knowledge, such as tuberculosis, have reemerged new technologies, and the continuing as a growing health threat. commitment of America’s biopharma- America’s biopharmaceutical research ceutical research companies can help companies are developing 394 medicines meet the continuing—and ever-changing and vaccines to combat the many threats —threat from infectious diseases. -
9-20-08 Referral
Comparative studies with antibiotics: Why should we change the rules? Paul M. Tulkens, MD, PhD Cellular and Molecular Pharmacology & Centre for Clinical Pharmacy Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium 10-10-2012 Late Phase Leaders Forum, Vienna, Austria 1 What its all about ? • We are in real need of novel antibiotics… but … most clinical studies with new compounds aim at equivalence or non-inferiority, failing to meet clinicians’ expectations and regulatory requirements for novelty. In parallel, safety issues are becoming an increasingly worrying hurdle for manufacturers Pricing make antibiotic unattractive • What are the possible solutions ? 10-10-2012 Late Phase Leaders Forum, Vienna, Austria 2 The antibiotic crisis * * A pictorial view using 4 paintings of Van Gogh (who stayed briefly in Belgium when moving from Holland to France) and with selected Belgian and International data… 10-10-2012 Late Phase Leaders Forum, Vienna, Austria 3 Are antibiotics following a path to madness ? discovery in soil bacteria and fungi 1928 - … 10-10-2012 Late Phase Leaders Forum, Vienna, Austria 4 Are antibiotics following a path to madness ? and then we all saw the blooming tree of semi- synthetic and totally synthetic antibiotics 1950 – 1980 … 10-10-2012 Late Phase Leaders Forum, Vienna, Austria 5 Are antibiotics following a path to madness ? and the US General Surgeon told us that the fight was over 1970 … 10-10-2012 Late Phase Leaders Forum, Vienna, Austria 6 Are antibiotics following a path to madness ? But… 2012 … 10-10-2012 Late Phase Leaders Forum, Vienna, Austria 7 Extent of resistance of P. -
Curriculum Vitae, Nils G. Walter, Dr. Ing. (Chemistry)
Curriculum Vitae, Nils G. Walter, Dr. Ing. (Chemistry) Department of Chemistry, Rm. 2405 Phone: (734) 615-2060 930 N. University Ave. FAX: (734) 647-4865 University of Michigan E-mail: [email protected] Ann Arbor, MI 48109-1055 http://singlemolecule.lsa.umich.edu http://sites.lsa.umich.edu/walter-lab https://rna.umich.edu PROFESSIONAL EXPERIENCE FACULTY 2020-present Faculty Director of the Microscopy Core in the Biomedical Research Core Facilities (BRCF) 2018 Sabbatical Visitor, Chan Zuckerberg Biohub, San Francisco 2017-present Francis S. Collins Collegiate Professor of Chemistry, Biophysics, and Biological Chemistry, College of Literature, Science and the Arts 2016-present Founding Co-Director, Center for RNA Biomedicine, U. of Michigan; awarded a 5-year $10.2M Biosciences Initiative Award in 2018 to further build this grassroots, 150-faculty member effort 2016-present Professor of Biological Chemistry 2015-present Co-Director, Microfluidics in Biomedical Sciences Training Program 2015-present Associate Director, Michigan Post-baccalaureate Research Education Program (PREP) 2010-present Founding Director, Single Molecule Analysis in Real-Time (SMART) Center 2009-present Professor of Chemistry 2005-2009 Associate Professor of Chemistry 2006 Sabbatical Visitor, Harvard University, with Sunney Xie in Chemistry & Chemical Biology 2006 Distinguished Visitor, JILA, Boulder, with David Nesbitt 2002-2005 Dow Corning Assistant Professor of Chemistry 1999-2005 Assistant Professor of Chemistry 1999-present Member of the Biophysics (since 1999), Applied Physics (since 2000), Cellular & Molecular Biology (since 2001), and Chemical Biology (since 2005) Interdepartmental Graduate Programs University of Michigan, Ann Arbor POSTDOCTORATE 1996-1999 Postdoctoral Research Fellow with Prof. John M. Burke, University of Vermont; Subject: Biophysical Studies of the Hairpin Ribozyme 1995 Postdoctoral Research Fellow with Nobel laureate Prof. -
Interview with Melvin I. Simon
MELVIN I. SIMON (b. 1937) INTERVIEWED BY SHIRLEY K. COHEN May 24 and June 5, 2005 Melvin I. Simon ARCHIVES CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California Subject area Biology Abstract Interview in two sessions, May 24 and June 5, 2005, with Melvin I. Simon, Anne P. and Benjamin F. Biaggini Professor of Biological Sciences, emeritus, in the Division of Biology. Dr. Simon received his BS from City College of New York in 1959 and his PhD in biochemistry from Brandeis in 1963. After receiving his degree, he was a postdoctoral fellow with Arthur Pardee at Princeton for a year and a half and then joined the faculty of the University of California at San Diego. In 1978, Dr. Simon and his UCSD colleague John Abelson established the Agouron Institute in San Diego, focusing on problems in molecular biology. He (along with Abelson) joined the faculty of Caltech as a full professor in 1982, and he served as chair of the Biology Division from 1995 to 2000. http://resolver.caltech.edu/CaltechOH:OH_Simon_M In this interview, he discusses his education in Manhattan’s Yeshiva High School (where science courses were taught by teachers from the Bronx High School of Science), at CCNY, and as a Brandeis graduate student working working with Helen Van Vunakis on bacteriophage. Recalls his unsatisfactory postdoc experience at Princeton and his delight at arriving at UC San Diego, where molecular biology was just getting started. Discusses his work on bacterial organelles; recalls his and Abelson’s vain efforts to get UCSD to back a full-scale initiative in molecular biology and their subsequent founding of their own institute. -
Computational Antibiotics Book
Andrew V DeLong, Jared C Harris, Brittany S Larcart, Chandler B Massey, Chelsie D Northcutt, Somuayiro N Nwokike, Oscar A Otieno, Harsh M Patel, Mehulkumar P Patel, Pratik Pravin Patel, Eugene I Rowell, Brandon M Rush, Marc-Edwin G Saint-Louis, Amy M Vardeman, Felicia N Woods, Giso Abadi, Thomas J. Manning Computational Antibiotics Valdosta State University is located in South Georgia. Computational Antibiotics Index • Computational Details and Website Access (p. 8) • Acknowledgements (p. 9) • Dedications (p. 11) • Antibiotic Historical Introduction (p. 13) Introduction to Antibiotic groups • Penicillin’s (p. 21) • Carbapenems (p. 22) • Oxazolidines (p. 23) • Rifamycin (p. 24) • Lincosamides (p. 25) • Quinolones (p. 26) • Polypeptides antibiotics (p. 27) • Glycopeptide Antibiotics (p. 28) • Sulfonamides (p. 29) • Lipoglycopeptides (p. 30) • First Generation Cephalosporins (p. 31) • Cephalosporin Third Generation (p. 32) • Fourth-Generation Cephalosporins (p. 33) • Fifth Generation Cephalosporin’s (p. 34) • Tetracycline antibiotics (p. 35) Computational Antibiotics Antibiotics Covered (in alphabetical order) Amikacin (p. 36) Cefempidone (p. 98) Ceftizoxime (p. 159) Amoxicillin (p. 38) Cefepime (p. 100) Ceftobiprole (p. 161) Ampicillin (p. 40) Cefetamet (p. 102) Ceftoxide (p. 163) Arsphenamine (p. 42) Cefetrizole (p. 104) Ceftriaxone (p. 165) Azithromycin (p.44) Cefivitril (p. 106) Cefuracetime (p. 167) Aziocillin (p. 46) Cefixime (p. 108) Cefuroxime (p. 169) Aztreonam (p.48) Cefmatilen ( p. 110) Cefuzonam (p. 171) Bacampicillin (p. 50) Cefmetazole (p. 112) Cefalexin (p. 173) Bacitracin (p. 52) Cefodizime (p. 114) Chloramphenicol (p.175) Balofloxacin (p. 54) Cefonicid (p. 116) Cilastatin (p. 177) Carbenicillin (p. 56) Cefoperazone (p. 118) Ciprofloxacin (p. 179) Cefacetrile (p. 58) Cefoselis (p. 120) Clarithromycin (p. 181) Cefaclor (p. -
NEW ANTIBACTERIAL DRUGS Drug Pipeline for Gram-Positive Bacteria
NEW ANTIBACTERIAL DRUGS Drug pipeline for Gram-positive bacteria Françoise Van Bambeke, PharmD, PhD Paul M. Tulkens, MD, PhD Pharmacologie cellulaire et moléculaire Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium http://www.facm.ucl.ac.be Based largely on presentations given at the 24th and 25th European Congress of Clinical Microbiology and Infectious Diseases and the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 1 Disclosures Research grants for work on investigational compounds discussed in this presentation from • Cempra Pharmaceuticals • Cerexa • GSK • Melinta therapeutics • The Medicine Company • MerLion Pharmaceuticals • Theravance • Trius 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 2 Belgium 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 3 Belgium 10 millions inhabitants … 10 Nobel prizes (10/850) • Peace - Institute of International Law, Ghent (1904) - Auguste Beernaert (1909) - Henri Lafontaine (1913) - Father Dominique Pire (1958) • Literature - Maurice Maeterlinck, Ghent (1911) • Medicine - Jules Bordet, Brussels (1919) - Corneille Heymans, Ghent (1938) - Christian de Duve, Louvain (1974) - Albert Claude, Brussels (1974) • Chemistry - Ilya Prigogyne, Brussels (1977) - Physics - François Englert, Brussels (2013) 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 4 The Catholic University of Louvain in brief (1 of 4) • originally founded in 1425 in the city of Louvain (in French and English; known as Leuven in Flemish) 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 5 The Catholic University of Louvain in brief (2 of 4) • It was one of the major University of the so-called "Low Countries" in the 1500 – 1800 period, with famous scholars and discoverers (Vesalius for anatomy, Erasmus for philosophy, …). -
How a Chemist Looks at RNA Thomas R
Angewandte Chemie DOI: 10.1002/anie.201205427 RNA Chemistry How a Chemist Looks at RNA Thomas R. Cech* 1989 chemical genetics · kinetics · RNA · thermo- dynamics I was passing through customs some time ago, returning from splicing reaction.[5] At the same time, it became increasingly London. The immigration officer, seemingly unsatisfied with clear that rRNA must have an active role in protein syn- my self-identification as “professor,” inquired about my thesis,[6] which was later confirmed in atomic detail by X-ray research area. “Molecular biology,” I answered; then added crystallography.[7] Evolution-in-a-test-tube experiments “ribonucleic acid,” certain this would convince him that I was showed that the potential versatility of RNA far exceeded harmless. the examples found in nature thus far,[8] adding credibility to At other times I identify myself as a biochemist, but the idea of a primordial “RNA World” where RNA served as almost never as just-plain chemist. This may seem a bit odd, both genetic material and as catalyst. given that all of my formal degrees (B.A. Grinnell College, The next rush of RNA discoveries concerned RNA as Ph.D. UC Berkeley) are in Chemistry, my first (and only) a regulator of gene expression. It had previously been thought faculty appointment has been in a Department of Chemistry, that most regulation was conducted by proteins that either and I teach General Chemistry to undergraduates. The repressed or activated gene transcription (the DNA!RNA opportunity to write something to help celebrate 125 years step) or regulated mRNA stability or translation (the RNA! of Angewandte Chemie has prompted me to organize some protein step). -
Dashawn Hickman
DaShawn Antwane Hickman 2816 Edgehill Road |Cleveland Heights, OH 44118 Phone: (203) 873-8344 |Email: [email protected] Education Case Western Reserve University, Cleveland, OH Doctor of Philosophy (Ph.D) expected May 2017 Doctor of Medicine (M.D.) expected May 2019 Yale University, New Haven, CT Bachelor of Science, Biomedical Engineering Awarded May 2009 A.C. Flora High School, Columbia, SC High School Diploma Awarded May 2005 International Baccalaureate Diploma Awarded May 2005 Research Department of Biomedical Engineering, Case Western Reserve University, Graduate Student Experience Cleveland, OH, May 2013-August 2015 § Principle Investigator: Erin Lavik, ScD § Synthesize polymer based hemostatic nanoparticles § Characterize nanoparticles using dynamic light scattering and ultra performance liquid chromatography § Validate efficacy and safety of treatments in rodent and porcine animal models § Investigate the immune response (CARPA) to hemostatic nanoparticles Department of Internal Medicine/Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Research Technician Little Rock, AR, Feb 2011-May 2011 § Principle Investigator: Jonathan Dranoff, MD § Perform functional and molecular studies on bile duct epithelia and portal fibroblast § Develop models examining the interaction of bile duct epithelia and portal fibroblast § Independent Literature Review § Present research in formal lab meetings Department of Internal Medicine/Digestive Diseases, Yale University, Postgraduate Associate New Haven, CT, July -
Curriculum Vitae
1 CURRICULUM VITAE David Ross Engelke EDUCATION 1974 University of Wisconsin, Madison, B.S. (Biochemistry) 1979 Washington University, St. Louis, Ph.D. (Biological Chemistry) Advisor: Robert G. Roeder POSTDOCTORAL TRAINING 1979-1983 Postdoctoral Fellow, Department of Chemistry, University of California, San Diego, La Jolla, California, Advisor: John Abelson ACADEMIC APPOINTMENTS 1983-1989 Assistant Professor, Department of Biological Chemistry, The University of Michigan, Ann Arbor, Michigan 1989-1996 Associate Professor, Department of Biological Chemistry, The University of Michigan 1996-2015 Professor, Department of Biological Chemistry, University of Michigan 1995 Interim Director, Medical Scientist Training Program 1995-1998 Director, Cellular and Molecular Biology Ph.D. Program, The University of Michigan 1998-2007 Founding Director, Program in Biomedical Sciences, The University of Michigan 2000-2007 Assistant Dean, Graduate and Postdoctoral Studies, UM Medical School 2008-2012 Associate Dean, H. H. Rackham School of Graduate Studies University of Michigan 2009-2010 Founding Director, Michigan Postbaccalaureate Research Education Program (PREP) 2010-2015 Associate Director, Michigan PREP 2013-2015 Chair, Department of Biological Chemistry, University of Michigan 2015-present Professor of Chemistry, University of Colorado Denver | Anschutz Professor of Biochemistry and Molecular Genetics, UC Denver | Anschutz Dean of the Graduate School, UC Denver | Anschutz CONSULTING POSITIONS 1989-1994 Parke-Davis 1990/91 Merck Inc. 1994 NeXstar, -
Determinants of the Species Selectivity of Oxazolidinone Antibiotics Targeting the Large Ribosomal Subunit
DOI 10.1515/hsz-2013-0188 Biol. Chem. 2013; 394(11): 1529–1541 Jagmohan S. Saini, Nadine Homeyer, Simone Fullea and Holger Gohlke* Determinants of the species selectivity of oxazolidinone antibiotics targeting the large ribosomal subunit Abstract: Oxazolidinone antibiotics bind to the highly Introduction conserved peptidyl transferase center in the ribosome. For developing selective antibiotics, a profound under- Ribosomes are complex nanomachines that perform standing of the selectivity determinants is required. We protein synthesis in all living cells. This pivotal role makes have performed for the first time technically challenging the bacterial ribosome a prominent target for antibiotics molecular dynamics simulations in combination with that exert their antimicrobial effect by interfering with molecular mechanics Poisson-Boltzmann surface area protein synthesis (David-Eden et al., 2010). Several crystal (MM-PBSA) free energy calculations of the oxazolidinones structures of ribosomal subunits bound to different classes linezolid and radezolid bound to the large ribosomal sub- of antibiotics have been published over the last decade units of the eubacterium Deinococcus radiodurans and revealing the binding site and binding mode in atomic the archaeon Haloarcula marismortui. A remarkably good detail as well as the structural basis for antibiotic specific- agreement of the computed relative binding free energy ity (Brodersen et al., 2000; Carter et al., 2000; Bottger et al., with selectivity data available from experiment for lin- 2001; Schlunzen et al., 2001; Hansen et al., 2003; Yonath, ezolid is found. On an atomic level, the analyses reveal an 2005a; Ippolito et al., 2008; Wilson et al., 2008; Belousoff intricate interplay of structural, energetic, and dynamic et al., 2011). -
Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .