Chemotherapy of Fungal Diseases

567 Pages·1990·17.4 MB·English

by  John F. Ryley (auth.)

Handbook of
Experimental Pharmacology
Volume 96
Editorial Board
G.y' R. Born, London
P. Cuatrecasas, Ann Arbor, MI
H. Herken, Berlin
Chemotherapy of
Fungal Diseases
Contributors
Donald Armstrong, F. Thomas Boyle, Manuel Debono
Bertrand Dupont, Sarah C. Eardley, Oliver P. Flint
Robert S. Gordee, John R. Graybill, Heinz Hanel
Thomas C. Jones, David Kerridge, Ann Lambert
David Loebenberg, Philip A. Pizzo, Annemarie Polak
Wolfgang Ritter, Marguerite M. Roberts
William R. Robertson, John F. Ryley, Heinz J. Schmitt
Jack D. Sobel, John J. Stern, Alan M. Sugar, Michael H. Tarbit
Hugo Vanden Bossche, Violette V. Villars, Thomas J. Walsh
Robert G. Wilson, Michel Zaug
Editor
,
John F. Ryley
Springer-Verlag
Berlin Heidelberg N ew York
London Paris Tokyo
HO'ng Kong Barcelona
JOHN F. RYLEY
ICI Pharmaceuticals
Mereside, Alderley Park,
Macclesfield, Cheshire SKIO 4TG
England
With 72 Figures
ISBN-I3 :978-3-642-75460-9 e-ISBN-I3 :978-3-642-75458-6
DOl: 10.1007/978-3-642-75458-6
Library of Congress Cataloging-in-Publication Data. Chemotherapy of fungal diseases/contributors,
Donald Armstrong ... let al.]; editor, John F. Ryley. p. cm. - (Handbook of experimental pharma
cology: v. 96) Includes bibliographical references. ISBN-13:978-3-642-7S460-9 (U .S.: alk.paper): 1.Antifungal
agents. 2. Mycoses - Chemotherapy. I. Armstrong, Donald, 1931- . II. Ryley, J. F. (John Frederick),
1928- . III. Series. [DNLM: 1. Antifungal Agents - therapeutic use. 2. Mycoses - drug therapy. WI
HASIL v. 96/WC 4S0 CS17] QP90S.H3 vol. 96 [RM41O] 6IS'. 1 s-dc20 [616.9'69061] DNLM/
DLC for Library of Congress 90-9471 CIP
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List of Contributors
DONALD ARMSTRONG, Infectious Disease Section, Memorial Sloan-Kettering
Cancer Center, 1275 York Avenue, New York, NY 10021, USA
F. THOMAS BOYLE, ICI Pharmaceuticals, Mereside, Alderley Park, Maccles
field, Cheshire SK10 4TG, England
MANUEL DEBONO, Lilly Research Laboratories, Lilly Corporate Center,
Indianapolis, IN 46285, USA
BERTRAND DUPONT, Pasteur Institute, Infectious Disease Unit and Mycology
Unit, 25 Rue du Dr. Roux, F-75015 Paris, France
SARAH C. EARDLEY, ICI Pharmaceuticals, Mereside, Alderley Park, Maccles
field, Cheshire SKI0 4TG, England.
OLIVER P. FLINT, ICI Pharmaceuticals, Mereside, Alderley Park, Maccles
field, Cheshire SK10 4TG, England. Present address: Bristol-Myers
Squibb PRDD, P.O. Box 4755, Syracuse, NY 13221-4755, USA
ROBERT S. GORDEE, Lilly Research Laboratories, Lilly Corporate Center,
. Indianapolis, IN 46285, USA
JOHN R. GRAYBILL, Audie L. Murphy Memorial Veterans Hospital, 7400
Merton Minter Boulevard, San Antonio, TX 78284, USA
HEINZ HANEL, Hoechst Aktiengesellschaft, Postfach 8003 20, 6230 Frankfurt
am Main 80, FRG
THOMAS C. JONES, Allergy and Infectious Diseases, Clinical Research,
Sandoz Ltd., Basle 4002, Switzerland
DAVID KERRIQGE, Department of Biochemistry, Tennis Court Road, Cam
bridge CB21QW, England
ANN LAMBERT, Department of Medicine (Clinical Biochemistry), Hope Hos
pital, Eccles Old Road, Salford M6 8HD, England
DAVID LOEBENBERG, Schering Research, Schering-Plough Corporation, 60
Orange Street, Bloomfield, NJ 07003, USA
PHILIP A. PIZZO, Infectious Diseases Section, Pediatric Branch, National
Cancer Institute, Bethesda, MD 20892, l,JSA
VI List of Contributors
ANNEMARIE POLAK, Pharmaceutical Research Division, F. Hoffmann-La
Roche Ltd., 124 Grenzacherstrasse, 4002Basel, Switzerland
WOLFGANG RI'ITER, Bayer AG, Institut fUr Klinische Pharmakologie,
Aprather Weg, Postfach 10 1709,5600 Wuppertal 1, FRG
MARGUERITE M. ROBERTS, The Skin Hospital, Out-Patients Department
(University of Manchester School of Medicine), Chapel Street, Salford,
Lanes M60 9EP, England
WILLIAM R. ROBERTSON, Department of Medicine (Clinical Biochemistry),
Hope Hospital, Eccles Old Road, Salford M6 8HD, England
JOHN F. RYLEY, ICI Pharmaceuticals, Mereside, Alderley Park, Macclesfield,
Cheshire SK10 4TG, England
HEINZ J. SCHMITT, Kinderklinik der UniversiHit, Langenbeckstrasse, 6500
Mainz, FRG
JACK D. SOBEL, Division of Infectious Diseases, Suite 202 Professional
Building, Harper Hospital, 4160 John R, Detroit, MI 48201, USA
JOHN J. STERN, Buckley Medical Associates, Pennsylvania Hospital, 822 Pine
Street, Philadelphia, PA 19107, USA
ALAN M. SUGAR, Section of Infectious Diseases, Evans Memorial Depart
ment of Clinical 'Research, The University Hospital, 88 East Newton
Street, Boston, MA 02118-2393, USA
MICHAEL H. TARBIT, Department of Bichemical Pharmacology, Glaxo Group
Research, Ware, Hertfordshire SG12 ODP, England
HUGO VANDEN BOSSCHE, Department of Comparative Biochemistry, Janssen
Research Foundation, Turnhoutseweg 30, B-2340 Beerse, Belgium
VIOLETTE V. VILLARS, Allergy and Infectious Diseases, Clinical Research,
Sandoz Ltd., Basle 4002, Switzerland
THOMAS J. WALSH, Infectious Diseases Section, Pediatrics Branch, National
Cancer Institute, Bethesda, MD 20892, USA
ROBERT G. WILSON, ICI Pharmaceuticals, Mereside, Alderley Park, Maccles
field, .Cheshire SK10 4TG, England
MICHEL ZAUG, Pharmaceutical Research Division, F. Hoffmann-La Roche
Ltd., 124 Grenzacherstrasse, 4002 Basel, Switzerland
Preface
Fungal diseases have been with us from antiquity; interest in the chemo
therapy of fungal disease has exploded in the past decade. To plan and pro
duce a book on the topic of antifungal chemotherapy has come as a personal
challenge - and something of an eye-opener - towards the end of my re
search career. A landmark publication which still merits reading is Antifungal
Chemotherapy (John Wiley & Sons, Chichester, UK), edited by David
Speller, which appeared in 1980. However, the fact that ketoconazole, the
first of the modern, orally active, wide-spectrum antifungals, attracted no
more than two sentences in it indicates just how far we have come in the 1980s.
A steady stream of original papers and a number of conference proceedings
have chronicled this progress in drug research; outstanding among the latter
are the proceedings of an international telesymposium, entitled Recent Trends
in the Discovery, Development and Evaluation of Antifungal Agents, edited
by Robert Fromtling (J.R. Prous, Barcelona, 1987) and volume 544 of the
Annals of the New York Academy of Sciences, entitled Antifungal Drugs,
edited by Vassil St. Georgiev, and containing papers and posters presented
at a most enjoyable 3-day conference held at Garden City, New York, in the
autumn of 1987.
Why then a new book? The Telesymposium Proceedings, and to a lesser
extent tbe New York Academy of Sciences volume, are product-oriented
works dealing with recently marketed compounds and some still in develop
ment. Although tremendous strides in antifungal chemotherapy have been
made during the last decade, and although many conditions can now be suc
cessfully treated, the problems of fungal disease remain and are, in fact,
increasing. This is because potential sources of infection are widespread, and
fungal infection is often the consequence of another illness or predisposing
cause in the patient. Advances in high-technology medicine, a greater use of
antibiotics, increasingly aggressive chemotherapy of malignant conditions,
organ transplantation with its associated immunosuppression and the ever
growing incidence of AIDS have all contributed to the burgeoning prevalence
of opportunistic mycoses. Against this background of continuing need, I have
tried to produce a volume which will chart the processes involved in the dis
covery, development and final clinical utilisation of a new drug. My aim has
not been to produce a series of specialist chapters for specialists but rather a
volume which will help the specialist involved at just one stage of the complex
VIII Preface
process of drug discovery and development to appreciate the need for and
contributions to be made by the many others involved in the overall process
before a new drug is successfully established.
In planning this volume I have particularly had in mind five groups of
people: the experimentalist, the "middleman", the clinician, the manager and
the academic. In the first group I hope to stimulate a reappraisal of screening
methodology based on recent experience, suggest new approaches to drug
discovery, make them more aware of the complex processes involved before
a product of their research can become an acceptable drug and present the
challenges of the ever-changing clinical needs. I trust the experts involved in
the various stages of drug development, who are not necessarily experts in
matters mycological, might find useful background information on both re
search and clinical matters which would stimulate them as they make their
vital contribution to the complete scheme. It is easy for a clinician to prescribe
a drug in areas of medicine for which plenty of alternative therapies are avail
able. I hope the clinician faced with fungal diseases, perhaps frustrated by the
limited choices available, will find in this volume some reminder of the cost
both in terms of money, time and scientific effort required before a new drug
can be added to his armamentarium. It must be an awesome decision for any
management to take to enter a new area of medicinal research; to discover,
develop and launch a new drug might cost at today's prices something in
the region of £100 million, money which will have to be recouped from sales
before any hope of profit is possible. My wish is that this book will remind
managers of the urgent needs and opportunities in the field of antifungal
chemotherapy as well as of the ideas and processes by which these needs might
be met. Often with little experience or understanding of the pressures and
issues in industry, academics will hopefully come to appreciate better the
complexity and cost of the processes of drug discovery, and particularly of
drug development, and to see where in the general scheme of things they can
make their most valuable contribution.
I am most grateful to the many friends from academic and clinical situa
tions who have so readily come to my rescue and written chapters on their
own particular specialities. Two pharmaceutical companies in particular have
had a great deal of recent experience taking new compounds from the
laboratory to the clinic. I had planned for the drug development section of
this book to have a series of chapters written jointly by experts from these two
establishments based on their recent experiences. In the event collaboration
was not forthcoming, and my grand design was frustrated. I am particularly
grateful, therefore, to the friends and colleagues from other parts of industry
- and to their helpful and co-operative managements - who have not only
rescued me from my predicament but have also contributed so generously to
the other two sections of the book.
Preface IX
As so as we begin the last decade of the twentieth century, it is my hope
that this volume will in some way stimulate research into new ways of meeting
the continuing challenge of fungal diseases and promote better understanding
between those involved at the practical level in discovering and progressing a
new treatment.
Alderley Park JOHN F. RYLEY
Contents
SECTION I. Drug Discovery
Introduction
JOHN F. RYLEY 1
CHAPTER 1
Drug Discovery: A Chemist's Approach
F.THOMAS BOYLE. With 8 Figures. . ...... . .... . .............. ..... 3
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
B. Development of a Lead ...................................... 4
C. Identification of a Lead ...................................... 14
I. Fungal Sterol Metabolism - A Target for Lead Identification . . 14
II. Ll24 - Transmethylation in Yeast and Fungal Sterol Synthesis ... 18
III. Regulation of Ll24- Transmethylation. . . . . . . . . . . . . . . . . . . . . . . 19
IV. In House Lead Structure Selection and Biological Investigations 21
D. Concluding Remarks ........................................ 27
References ............ :....................................... 28
CHAPTER 2
Drug Discovery: A Biochemist's Approach
DAVID KERRIDGE and HUGO VANDEN BOSSCHE. With 10 Figures 31
A. Introduction................................................ 31
B. Factors Affecting the Choice of Target ......................... 34
I. The Cell Wall as a Barrier to Drug Uptake .................. 35
C. Potential Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 36
I. External to the Plasma Membrane ......................... 36
1. Structural Polysaccharides ............................. 36
2. Cell Wall Associated Enzymes. . . . . . . . . . . . . . . . . . . . . . . . .. 37
3. Plasma Membrane Associated Targets ................... 39
II. Internal Targets. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 45
1. Transport of Drugs into Sensitive Fungi .................. 45
2. Plasma Membrane Proteins ............................ 48
XII Contents
3. Pathways of Intermediary Metabolism ................... 56
4. Macromolecular Synthesis ............................. 62
III. Miscellaneous Targets ................................... 63
1. Drugs Preventing Adhesion ............................ 63
2. Dimorphism ......................................... 64
3. The Cytoskeleton. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 64
4. Exocellular Compounds Involved in Disease . . . . . . . . . . . . .. 65
IV. Which Target? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 65
D. Short-Term Solutions to Antifungal Therapy .................... 66
I. Combination Therapy ................................... 66
II. Drug Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 67
E. Long-Terms Developments.. . ....... . ....... ...... . . . .... . ... 67
References .................................................... 68
CHAPTER 3
Drug Discovery: Nature's Approach
MANUEL DEBONO and ROBERT S. GORDEE. With 2 Figures
II. Marine Organisms ...................................... .
C. The Fungal Cell Wall as an Antifungal Target .................. .
I. Biomolecular Composition and Approaches to Screening for
Inhibition of Cell Wall Biosynthesis ....................... . 90
II. Inhibition of ~-(1,3)-Glucan Synthesis ..................... . 92
III. Inhibitors of Chitin Synthase ............ _. ................ . 95
D. Biological Evaluation of Antifungal Agents .................... . 99
E. Conclusion ................................................ . 102
References ................................................... . 103
CHAPTER 4
Screening and Evaluation In Vitro
ROBERTG. WILSON and JOHN F. RyLEy ............................. 111
A. Purpose of Screening ........................................ 111
B. Methods of Screening. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 112
C. Choice of Organisms and Conditions ........................... 113
D. Choice of Media ............................................ 113
E. A Workable In Vitro Screen .................................. 115
F. Interpretation of Screen Results ............................... 117
G. Relevance of Screen ......................................... 117
H. Evaluation In Vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 120
J. Features of Activity ......................................... 122