Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery

392 Pages·2001·8.776 MB·English

by  Philip J. Rosenthal, Louis H. Miller (auth.), Philip J. Rosenthal MD (eds.)

Antimalarial Chemotherapy
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n f e c t 1• o u s Di s e a s e
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SERIES EDITOR: Vassil St. Georgiev
Natiollailnstitlfte of Allergy and Infectiolls Diseases
Nationai lnstitlltes of Healtll
Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New
Directions in Drug Discovery, edited by Philip J. Rosenthal, MD, 2001
Retroviral Immunology: Immune Response alld Restoration, edited by Giuseppe
Pantaleo, MD and Bruce D. Walker, MD, 200 I
Drug Interactions in Infectious Diseases, edited by
Stephen C. Piscitelli, PllarmD and Keith A. Rodvold, PllarmD, 2001
Management of Antimicrobials in Infectious Diseases: Impact ofA ntibiotic
Resistance, edited by Arch G. Mainous III, PhD and Claire Pomeroy, MD, 2001
Infectious Disease in the Aging: A Clinical Handbook, edited by
Thomas T. Yoshikawa, MD and Deall C. Norman, MD, 2001
Infectious Causes of Cancer: Targets for lnrervem;on, edited by
James J. Goedert, MD,2000
Antimalarial
Chemotherapy
Mechanisms of Action, Resistance,
and New Directions in Drug Discovery
Edited by
Philip J. Rosenthal, MD
School of Medicine, University of California, San Francisco, CA
Springer-Science+Business Media, LLC
© 2001 Springer Science+Business Media New York
Originally published by Humana Press Inc in 200 I
Softcover reprint of the hardcover I st edition 200 I
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Totowa, New Jersey 07512
All rights reserved.
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means,
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All authored papers, comments, opinions, conclusions, or recommendations are those of the author(s), and do not
necessarily reflect the views of the publisher.
Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the
information published and to describe generally accepted practices. The contributors herein have carefully checked to
ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted
at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from
clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the
product information provided by the manufacturer of each drug for any change in dosages or for additional warnings
and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used
drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual
patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status
of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors
or omissions or for any consequences from the application of the information presented in this book and make no
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Cover design by Patricia F. Cleary.
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10 9 8 7 6 5 4 3 2 I
Library of Congress Cataloging in Publication Data
Antimalarial chemotherapy: mechanisms of action, resistance, and new directions in drug discovery / edited by
Philip 1. Rosenthal.
p. ; em. --(Infectious disease)
Includes bibliographical references and index.
ISBN 978-1-61737-124-0 ISBN 978-1-59259-111-4 (eBook)
DOI 10.1007/978-1-59259-111-4.
I. Antimalarials. I. Rosenthal, Philip J. II. Infectious
disease (Totowa, N.J.)
[DNLM: 1. Antimalarials-pharmacology. 2. Drug Resistance. 3.
Malaria---drug therapy. QV 256 A6307 2001]
RC159.A5 A58 2001
616.9'362061--dc21
00-059762
Preface
We who are engrossed in the study of antimalarial chemotherapy are fond
of repeating certain maxims. Malaria is one of the most important disease prob
lems in the world. The control of malaria is increasingly limited by resistance
to available drugs. New strategies for treating malaria are urgently needed.
We should strive to identify new targets for antimalarial agents. Each of these
maxims has reached the status of a cliche, but is nonetheless compelling. The
complex biology of malaria parasites and extreme poverty in most malarious
regions have locked us into an unrelenting continuation of endemic malaria in
most of the tropical world. Meanwhile, drug resistance worsens, and it appears
that the speed of efforts to develop new treatment strategies may not keep pace
with the resourceful parasites. This rather bleak scenario presents us with major
challenges. For the short term, as drug resistance worsens and standard thera
pies fail, how will we utilize existing agents to prevent worsening of worldwide
malaria? Which strategies are likely to provide effective new antimalarial
drugs? And for the future, how can we develop strategies incorporating old
and new therapies and other control modalities to begin to lessen the world
wide burden of malaria?
Although challenges for the effective treatment and control of malaria are
great, so are current opportunities. Our understanding of the biology of malaria
parasites is growing rapidly. The entire genome of Plasmodium falciparum will
soon be sequenced. New molecular technologies are allowing us to definitively
assess the biological roles of key parasite molecules. There is good reason to
believe that these advances will speed up the pace of antimalarial drug discov
ery and development. As is discussed throughout this book, recent progress has
been impressive. New insights into the appropriate use of existing drugs and
optimal means of attacking known targets are being gained, and new potential
drug targets are being identified.
At this point, it seems appropriate to collect our current understanding of
antimalarial chemotherapy in a single volume. Much has changed since earlier
classic references on this subject. We have moved to a more rational approach to
antimalarial chemotherapy, where we are attempting to logically use existing
agents and to develop new drugs designed to target specific parasite pathways.
For this approach, a much better understanding of parasite biology is needed.
Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Direc
tions in Drug Discovery offers detailed discussions from experts in many areas.
As background, chapters on the biology of parasites highlight two key areas, the
plasmodial food vacuole and plasmodial transport mechanisms. The public
v
vi Preface
health consequences of current problems in antimalarial chemotherapy are also
reviewed. Established antimalarial drugs and new agents under development
are then discussed in detail. Our emphasis is not on summarizing established
drug usages, but rather to present current understanding of the mechanisms of
action and resistance of existing agents in order to help us design new strategies
to use these or related compounds. The last section of the book presents infor
mation on new compounds. These include agents that are related to existing
effective antimalarials and some new targets. The chosen targets represent a
small sample of potential new avenues for chemotherapy. It is hoped that the
discussions of parasite biology and chemotherapy provided in this book will
help to stimulate additional ventures in this direction. As is often mentioned
(in yet another cliche), additional funding for research on malaria will be
essential for the breadth of study required to develop multiple new drugs.
My editing of Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and
New Directions in Drug Discovery has been rather time-consuming, but very
rewarding in allowing me the opportunity to work with world leaders in all
areas of malaria chemotherapy, and in providing me with a privileged look at
the status of cutting edge research in this field. I wish to thank all of the authors
for their hard work in preparing excellent discussions on their respective topics.
Thanks are also in order to those who have helped me to choose specific topics
and authors and offered advice through the course of the book preparation
process. I'm afraid that I will certainly neglect some contributors, but special
thanks go to Steve Meshnick, Irwin Sherman, Hagai Ginsburg, Ioav
Cabantchick, Terrie Taylor, Peter Bloland, Chris Plowe, David Fidock, Tom
Wellems, Mike Gottlieb, Lou Miller, Steve Ward, Leann Tilley, and Piero
Olliaro. I thank members of my laboratory at UCSF and my collaborators in
Kampala, Uganda, for their inspiration and useful ideas. I remain indebted to
the late Jim Leech, who was the perfect mentor to start me on a path of antima
larial drug discovery. Lastly, I thank my wife, Kandice Strako, for her indul
gence and support during the hectic and seemingly never-ending editing
process. My hope is that this book will offer a useful review for those who
study malaria, and, more importantly, an entry point into antimalarial chemo
therapy for those new to this field. If this is the case, and we can help to expand
efforts toward antimalarial drug discovery and development, our labors will
certainly have been worthwhile.
Philip J. Rosenthal, MD
Contents
Preface ................................................................................................................... v
List of Contributors ........................................................................................... ix
I INTRODUCTION
1 The Need for New Approaches to Antimalarial Chemotherapy
Philip J. Rosenthal and Louis H. Miller ......................................................... 3
2 The History of Antimalarial Drugs
Steven R. Meshnick and Mary J. Dobson ..................................................... 15
3 Transport and Trafficking in Plasmodium-Infected Red Cells
Kasturi Haldar and Thomas Akompong ...................................................... 27
4 The Plasmodium Food Vacuole
Ritu Banerjee and Daniel E. Goldberg .......................................................... 43
5 Clinical and Public Health Implications of Antimalarial
Drug Resistance
Piero L. Olliaro and Peter B. Bloland .......................................................... 65
II ESTABLISHED ANTIMALARIAL DRUGS AND COMPOUNDS UNDER CLINICAL
DEVELOPMENT
6 Chloroquine and Other Quinoline Antimalarials
Leann Tilley, Paul Loria, and Mick Foley ................................................... 87
7 8-Aminoquinolines
Ralf P. Brueckner, Colin Ohrt, J. Kevin Baird,
and Wilbur K. Milhous .............................................................................. 123
8 Mechanisms of Quinoline Resistance
Grant Dorsey, David A. Fidock, Thomas E. Wellems,
and Philip J. Rosenthal ............................................................................. 153
9 Folate Antagonists and Mechanisms of Resistance
Christopher V. Plowe ..................................................................................... 173
10 Artemisinin and Its Derivatives
Steven R. Meshnick ......................................................................................... 191
Vl1
viii Contents
11 Atovaquone-Proguanil Combination
Akhil B. Vaidya ............................................................................................... 203
12 The Antimalarial Drug Portfolio and Research Pipeline
Piero L. Olliaro and Wilbur K. Milhous .................................................... 219
III NEW COMPOUNDS, NEW ApPROACHES, AND NEW TARGETS
13 Novel Quinoline Antimalarials
Paul A. Stocks, Kaylene J. Raynes, and Stephen A. Ward ...................... 235
14 New Antimalarial Trioxanes and Endoperoxides
Gary H. Posner, Mikhail Krasavin, Michael McCutchen,
Poonsakdi Ploypradith, John P. Maxwell, Jeffrey S. Elias,
and Michael H. Parker ............................................................................... 255
15 Antibiotics and the Plasmodial Plastid Organelle
Barbara Clough and R. J. M. (lain) Wilson ............................................... 265
16 Fresh Paradigms for Curative Antimetabolites
Pradipsinh K. Rathod ..................................................................................... 287
17 Iron Chela tors
Mark Loyevsky and Victor R. Gordeuk ...................................................... 307
18 Protease Inhibitors
Philip J. Rosenthal .......................................................................................... 325
19 Inhibitors of Phospholipid Metabolism
Henri Joseph Vial and Michele Calas .......................................................... 347
20 Development of New Malaria Chemotherapy by Utilization
of Parasite-Induced Transport
Annette M. Gero and Alexander L. Weis .................................................... 367
Index .................................................................................................................. 385
Contributors
THOMAS AKOMPONG, PHD • Departments of Pathology and Microbiology-Immunology,
Northwestern University Medical School, Chicago, IL
J. KEVIN BAIRD, PHD • US Navy Medical Research Unit, Parasitic Diseases
Program, American Embassy, Jakarta, Indonesia
RITU BANERJEE, BA • Departments of Molecular Microbiology and Medicine,
Howard Hughes Medical Institute, Washington University, St. Louis, MO
PETER B. BLOLAND, DVM, MPVM • Malaria Epidemiology Branch, Division of
Parasitic Diseases, Center for Infectious Diseases, Centers for Disease Control
and Prevention, Chamblee, GA
RALF P. BRUECKNER, MD· Division of Experimental Therapeutics, Walter Reed
Army Institute of Research, Silver Spring, MD
MICHELE CALAS, PHD • Laboratoire des Aminoacides, Peptides et Proteines,
Universite de Montpellier II, Montpellier Cedex, France
BARBARA CLOUGH, PHD • Division of Parasitology, The National Institute for Medical
Research, London, UK
MARY J. DOBSON, DPHIL • Wellcome Unit for the History of Medicine, Oxford
University, Oxford, UK
GRANT DORSEY, MD • Department of Medicine, San Francisco General Hospital
and University of California, San Francisco, CA
JEFFREY S. ELIAS, BA • Department of Chemistry, School of Arts and Sciences,
Johns Hopkins University, Baltimore, MD
DAVID A. FIDOCK, PHD • Department of Microbiology and Immunology, Albert
Einstein College of Medicine, Bronx, NY
MICK FOLEY, PHD • Department of Biochemistry, La Trobe University, Bundoora,
Australia
ANNETTE M. GERO, PHD • School of Biochemistry and Molecular Genetics,
University of New South Wales, Sydney, Australia
DANIEL E. GOLDBERG, MD, PHD • Departments of Molecular Microbiology and
Medicine, Howard Hughes Medical Institute, Washington University,
St. Louis, MO
VICTOR R. GORDEUK, MD • Center for Sickle Cell Disease, Howard University,
Washington, DC
KASTURI HALDAR, PHD • Departments of Pathology and Microbiology-Immunology,
Northwestern University Medical School, Chicago, IL
IX
x Contributors
MIKHAIL KRASAVIN, BA • Department of Chemistry, School of Arts and Sciences,
Johns Hopkins University, Baltimore, MD
PAUL LORIA, BSe (HONS) • Department of Biochemistry, La Trobe University,
Bundoora, Australia
MARK LOYEVSKY, PHD • Center for Sickle Cell Disease, Howard University,
Washington, DC
MICHAEL MCCUTCHEN, BA • Department of Chemistry, School of Arts and Sciences,
Johns Hopkins University, Baltimore, MD
JOHN P. MAXWELL, BA • Department of Chemistry, School of Arts and Sciences,
Johns Hopkins University, Baltimore, MD
STEVEN R. MESHNICK, MD, PHD • Department of Epidemiology, University
of Michigan School of Public Health, Ann Arbor, MI
WILBUR K. MILHOUS, PHD • Division of Experimental Therapeutics, Walter Reed
Army Institute of Research, Silver Spring, MD
LOUIS H. MILLER, MD • Laboratory of Parasitic Diseases, National Institute
of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
COLIN OHRT, MD • Division of Experimental Therapeutics, Walter Reed Army
Institute of Research, Silver Spring, MD
PIERO L. OLLIARO, MD, PHD • UNDP/WB/WHO Special Programme for Research
and Training in Tropical Diseases (TDR), World Health Organization,
Geneva, Switzerland
MICHAEL H. PARKER, PHD • Department of Chemistry, School of Arts and Sciences,
Johns Hopkins University, Baltimore, MD
CHRISTOPHER V. PLOWE, MD, MPH • Malaria Section, Center for Vaccine
Development, University of Maryland School of Medicine, Baltimore, MD
POONSAKDI PLOYPRADITH, PHD • Department of Chemistry, School of Arts and
Sciences, Johns Hopkins University, Baltimore, MD
GARY H. POSNER, PHD • Department of Chemistry, School of Arts and Sciences,
Johns Hopkins University, Baltimore, MD
PRADIPSINH K. RATHOD, PHD • Department of Biology, The Catholic University
of America, Washington, DC
KAYLENE J. RAYNES, MD • Department of Pharmacology and Therapeutics,
University of Liverpool, Liverpool, UK
PHILIP J. ROSENTHAL, MD • Department of Medicine, San Francisco General
Hospital and University of California, San Francisco, CA
PAUL A. STOCKS, MD • Department of Pharmacology and Therapeutics,
University of Liverpool, Liverpool, UK
LEANN TILLEY, PHD • Department of Biochemistry, La Trobe University,
Bundoora, Australia
AKHIL B. V AIDYA, PHD • Department of Microbiology and Immunology, MCP
Hahnemann School of Medicine, Philadelphia, PA
HENRI JOSEPH VIAL, PHD • Dynamique Moleculaire des Interactions
Membranaires, CNRS, Universite Montpellier II, Montpellier Cedex, France