Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases
The review analyses the results showing that technological advances in studying the specific target molecules in a cell allow to develop new effective drugs for the treatment of a number of human maladies. The new approach to the drug design is based In the data of enzyme structure. В огляді проанал...
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Інститут молекулярної біології і генетики НАН України
1994
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| Цитувати: | Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases / S. Craig // Биополимеры и клетка. — 1994. — Т. 10, № 6. — С. 65-71. — Бібліогр.: 44 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859765742236336128 |
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| author | Craig, S. |
| author_facet | Craig, S. |
| citation_txt | Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases / S. Craig // Биополимеры и клетка. — 1994. — Т. 10, № 6. — С. 65-71. — Бібліогр.: 44 назв. — англ. |
| collection | DSpace DC |
| container_title | Биополимеры и клетка |
| description | The review analyses the results showing that technological advances in studying the specific target molecules in a cell allow to develop new effective drugs for the treatment of a number of human maladies. The new approach to the drug design is based In the data of enzyme structure.
В огляді проаналізовано результати, які показують, що досягнення у вивченні специфічних молекул-мішеней клітини дозволяють розробляти ефективні лікарськи засоби для лікування багатьох захворювань людини. Встановлено, що новий підхід до розробки таких медикаментів базується на дослідженні структури молекули фермента.
Обзор анализирует результаты, показывающие, что достижения в изучении специфических молекул-мишеней клетки позволяют разрабатывать эффективные лекарственные средства для лечения многих заболеваний человека. Установлено, что новый подход к разработке таких медикаментов основан на исследовании структуры молекулы фермента.
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| format | Article |
| fulltext |
УДК 616—093/098:577.15
S. Craig
PURINE SALVAGE ENZYMES AS TARGETS
FOR THE CHEMOTHERAPEUTIC TREATMENT
OF PARASITIC DISEASES
The review analyses the results showing that technological advances in studying the spe
cific target molecules in a cell allow to develop new effective drugs for the treatment of
a number of human maladies. The new approach to the drug design is based In the data
of enzyme structure.
Rational drug discovery/desing. The traditional approach to the discovery
of new drugs has involved the screening of large numbers of compounds
or extracts for bioactivity against specific pathogens. This more or less
random approach has usually been conducted without knowledge of the
molecular targets within the pathogen or mode of action of the drugs.
Host toxicity is usually determined empirically, only after a bioactive sub
stance has been identified.
Another, more systematic approach to drug discovery begins with the
identification of a molecular target within the pathogenic organism. Tar
gets are usually selected because their functions are pivotal for survival
and thus, inhibition of those functions may be lethal for the pathogenic
organism. Appropriate targets may be either enzymes that catalyze uni
que metabolic pathways or enzymes that are present in both the host and
the pathogen. In the latter case, the enzymes may be pivotal only for
survival of the pathogen, or they might be of equal importance for both
the host and pathogen but are suitable targets because of differences in
the pharmacological responses to specific drugs. For all of these situati
ons, after the target molecule has been selected, the objective is to identi
fy details of molecular structure and/or function that can be exploited in
the discovery or design of low molecular weight compounds that will se
lectively bind to the target molecule of the pathogen. Well-designed com
pounds should be highly selective in their affinity for the target molecule
of the pathogen, as compared to molecules of the host and thus may be
used at therapeutic levels that are non-toxic to the host.
Technological approaches to rational drug desing. If a target mole
cule is an enzyme, traditional biochemical procedures are appropriate for
analyzing enzyme/drug interactions. For example, kinetic studies of the
affects of various concentrations of a drug as an inhibitor of the initial
velocity of an enzyme catalyzed reaction, provide information about whe
ther a compound competes for binding to the active site of an enzyme or
an enzyme substrate complex [1]. Such information can be useful for
the design of novel inhibitors. Furthermore, steady state kinetic studies
can enable the determination of the concentration for a compound (Ki)
at which half of the enzyme should be bound to the compound. This con
centration is directly related to the affinity of the compound for the tar
get molecule and is the minimum concentration that might be expected
to have any possibility of partially blocking the enzyme catalyzed reacti
on believed to be pivotal for the survival of the pathogenic organism. Al
though KiS can be determined using impure enzyme, this value, determined
in vitro, can be more than an order of magnitude below that required in
€> S. Craig, 1'994
ISSN 0233-7057. БИОПОЛИМЕРЫ И КЛЕТКА. 1994. Т. 10, № 6 65
vivo to kill half of the pathogenic organisms [2]. However, KiS provide
physical constants for quantitating the selective affinity of compounds for
the target enzyme of a pathogen, as opposed to the homologous enzyme
of a host organism. For enzymes that are unique to a pathogen, the Ki
provides a minimum concentration for testing the in vivo effectiveness
and pharmacological properties of a compound.
Enzyme structure based drug design utilizes structural details to
design inhibitors selective for the enzyme of the pathogen. By definition,
the determination of three-dimensional structure of the target enzyme is
necessary. This can require the purification of milligram quantities of
the target enzymes from both the host and the pathogen. Since many tar
get molecules are in relatively low abundance within the cells of the host
or pathogen, purification of these molecules from the native source is
often impractical. However, developments in molecular biology have enab
led the cloning of cDNA and the expression of high levels of enzymes
within bacteria, yeast, or insect cells. For example, at present, it is possib
le to produce recombinant enzymes at 20—60 % of the total soluble pro
teins in bacteria [3—6]. Thus, the acquisition of quantities of protein ade
quate for structural analysis (i. e. via NMR or X-ray crystallography)
is less problematical today than it has been in the recent past.
Selective inhibitors (often referred to as «lead compounds» or «le
ads») having, an affinity for a target enzyme may already be known. How
ever, even if «leads» have not formerly been identified, three-dimensio
nal structure provides physical data that can be exploited, using compu
ters and computational chemistry, in the selection of compounds that may
bind to the active site of an enzyme, from among thousands of commer
cially available compounds [7]. Occassionally, the target enzyme may be
similar enough to a related enzyme whose structure is known to enable
the use of a model of the enzyme's structure rather than the actual 3-di-
mensional structure for the computer based selection of new leads [8].
Empirical testing (kinetic studies as described above) will demonstrate
if any of these compounds are good «leads» with an affinity for the active
site of the target enzyme. Also, co-crystallization of the lead compounds
with the target enzymes of both the host and the pathogen enables three
dimensional analyses and the determination of molecular contacts and
atomic interactions between the lead compounds and the target enzymes.
This type of analysis may reveal differences in the enzymes of the host
and pathogen that can be exploited in the re-design of leads to enhance
their affinity for the target enzyme of the pathogen [9—11]. Thus, itera
tive crystallography, lead re-design, and inhibitor testing both in vitro and
in vivo can enable the design of a potent selective inhibitor of a target
enzyme of a pathogen. In theory, inhibitors designed this way have a
better chance for being developed as an effective and non toxic agent
for the treatment of the disease caused by the pathogen.
Molecular targets of paiasites for rationally designed drugs. The
vast majority of drugs in use today, for the treatment of diseases caused
by parasites, were identified by traditional methods requiring the random
screening of large numbers of compounds for bioactivity against the pa
rasites. Subsequently, the molecular targets of a few of these drugs have
been determined. For example, dihydrofolate reductase (DHFR) has been
shown to be the target of compounds used in the treatment of a number
of diseases. Several compounds, such as chloroguanide, pyrimethamine,
and trimethoprim, which bind to DHFR's are in therapeutic use for the
treatment of diseases caused by parasites [12]. Furthermore, various
other antifolates are being tested for the treatment of infections caused
by Pneumocystis carinii [13—14] and Toxoplasma gondii [13, 15]. These
two infectious agents are increasingly important because they often are
problematical for immunocompromised patients suffering from AIDS or
recovering from an organ transplant. Also, antifolates are used for the
treatment of Plasmodium falciparum, an etiologic agent for malaria [12,
16]. In^ addition to DHFR, other molecular targets have been identified
66 ISSN 0233-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1994. Т. 10, № 6
for drugs used in the treatment of parasitic diseases. These include the
ornithine decarboxylase of trypanosomes [17] and the heme polymerase
of malarial parasites [18—19]. Rational approaches to drug discovery
and design, as described above, can and are being emploved to discover*
novel, potent, nootoxic compounds that will be more effective than exis*
ting approved drugs for the treatment of diseases caused by parasites.
Purine salvage enzymes as a target for rational drug discovery/de-
sing. Due to their pivotal role for the survival of parasites, purine salvage
enzymes were proposed more than 25 years ago as potential targets for
the chemotherapeutic treatment of malaria [20, 21]. However, unlike
DHFR, purine salvage enzymes have yet to be demonstrated to be the tar
get of an approved drug used in the treatment of a disease caused by a
pathogen. During the past two decades, the purine salvage enzymes of a
number of different parasites have been investigated. These studies in
clude enzymes from the etiologic agents for human leishmaniasis [22],.
giardiasis [23], Chagas' disease [24], and schistosomiasis [25], as well
as bovine tritrichomoniasis [26]. These studies show that the parasites
examined lack the anabolic pathways needed for the de novo synthesis of
purines. Thus, these organisms are forced to rely exclusively upon salvage'
pathways for the purines [guanosine triphosphate (GTP) and adenosine
triphosphate (ATP)] needed in RNA and DNA synthesis and for high
energy phosphate bonds to drive cellular metabolism.
Hypoxanthine phosphoribosyltransferase [HPRT; IMP: pyrophosp
hate phosphoribosyltransferase, ES 2.4.2.8, also hypoxanthine-guanine
phosphoribosyltransferase (HGPRT) or hypoxanthine-guanine-xanthine
phosphoribosyltransferase (HGXPRT)] is. a purine salvage enzyme that
has been studied extensively. Complementary DNA (cDNA) encoding the
human, schistosomal, malarial, trypanosomal, tritrichomonal, and bacte
rial HPRT's have been cloned and sequenced ([27—32], respectively).
The human HPRT has been a subject of extensive investigation because
defects in this enzyme are known to be responsible for genetically inhe
rited gout and Lesch—Nyhan syndrome in humans [33, 34]. The symp
toms of these diseases, which range from deleterious to lethal, result
from inactivation of the human enzyme. This emplasizes the importance
of trying to minimize the interactions of drugs with the HPRT of mamma
lian hosts.
Leads for drugs targeted to HPRTs. The long range objective of the
majority of the investigations of parasite purine salvage pathways is to
discover or design compounds that will selectively inhibit the activity of
a pivotal enzyme. The hope is that such a compound could be developed
as a drug in the treatment of the parasitic disease. However, only in re
cent years has significant progress been made toward the identification
of lead compounds that selectively target the purine salvage ensvmes of
any parasite [2, 22, 35].
Allopurinol is a relative non-toxic analog of xanthine that is approved
for use in the treatment of gout in humans. In humans the target of allo
purinol is the xanthine oxidase enzyme which converts xanthine to uric
acid. Allopurinol has also been shown to kill leishmanial parasites [36].
The drug is salvaged by the PHRT enzyme into the nucleotide pools and
is eventually incorporated into RNA which leads indirectly to an inhibi
tion of protein synthesis. This mechanism is postulated to account for the
antiparasitic action of allopurinol [36]. Thus, allopurinol is probably ef
fective in the treatment of Leishmaniasis because it is salvaged and incor
porated into RNA by the parasite but not by the host. These results show
promise that other substrate analogs, that will selectively bind to the
HPRTs of parasites, might be designed or discovered.
Queen et al. [2] demonstrated that 6-mercaptopurine (an analog of
hypoxanthine) and 6-thioguanine were «potent competitive inhibitors» of
the malarial HPRT. Six-mercaptopurine is metabolized to 6-thiouric acid
(6-mercapto-2,8-purinediol) in humans [37]. Both 6-mercaptopurine and
6-thioguanine have been used therapeutically as antineoplastics in humans
ISSN 0233-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1994. Т. 10, № 6 5* 67
[37]. Kinetic studies indicate that both of these compounds may be slight
ly selective in their inhibition of the malarial HPRT as opposed to the
human enzyme. Thus, these compounds may be good leads for drugs tar
geted to the HPRT of parasites responsible for human malaria.
Recently, a new method has been reported for screening for leads
targeted to the HPRT's of parasites [35]. This method is referred to as
comparative complement selection and involves the rapid screening in
bacteria of purine analogs for the inhibition of the recombinant HPRT's
of parasites as compared to the recombinant human enzyme. The proce
dure uses the activity of a recombinant HPRT to complement genetic de
ficiencies of the host bacteria. The bacteria are unable to grow unless
they are expressing a recombinant HPRT. Thus, the effects of compounds
on the growth of these bacteria can be screened employing sterile, blank
antibiotic testing discs and methods similar to those used in standard
antibiotic susceptibility assays. Complement selection alone enables the
identification of compounds that affect the growth of bacteria expressing
a particular enzyme. However, direct comparisons with the effects on bac
teria expressing the recombinant human enzyme enable the identification
of compounds that selectively target the enzymes of the parasites.
Three-dimensional analysis: a prerequisite to enzyme structure based
drug design. Since most HPRT's are functional as dimers, with molecular
weights in excess of 40 kDa, the only practical method for determining
three-dimensional structure requires crystallization followed by analyses
of X-ray diffraction patterns. As of this date, the three dimensional struc
ture for a purine salvage enzyme has yet to be reported in the literature,
although the structure of orotate phosphoribosyltransferase, a distantly
related enzyme, was recently reported [38]. However, several laboratori
es are actively working on the structure for a number of different HPRT's.
For example, crystals which diffract X-ray to a resolution of less than
3 A have been generated for both the human and schistosomal HPRT's
(Focia' and Fletterick, personal communication). Thus, the structures of
several HPRT's may be available in the not too distant future. As soon
as these structures are available, will be possible to analyze the binding
of «lead compounds» identified in the complement selection assay and
to move directly into the next phase of enzyme structure based inhibitor
design and refinement.
The development of resistance to new drugs. Microbial pathogens,
including parasites, are notorious for their ability to develop resistance
to drugs. It is for this reason that so much effort is being directed today
i.toward the development of vaccines for the treatment of parasitic disea
ses. However, parasites seem to be extraordinarily adapted to surviving
the immune responses of their hosts. This helps to explain why there is
still not a single, completely effective vaccine in use today for the treat
ment of parasitic disease of humans.
The advantage of the rational approach to the discovery or design of
new drugs, over the traditional random screening method, is that the
target of the drug is known. If the target is an enzyme, it will need to
be cloned and expressed to enable 3-dimensional and kinetic studies. Thus,
even before a single new drug has been discovered, there is an normous
side benefit that will enable the rapid development of second generation
drugs to treat first generation drug-resistant strains that may appear in
the future. Specifically, PCR primers can be designed that will enable
the amplification and re-cloning of cDNA encoding the target enzyme of
drug resistant strains using available technology [39]. The sequence for
cDNA may immediately reveal point mutations and amino acid substitu
tions in the target enzyme that are responsible for the resistance to the
new drugs [16, 40]. The amino acid substitution (s) can be analyzed using
the known 3-dimensional structure for the target enzyme and interactive
computer graphic display systems to reveal the mechanism for alteration
of the binding of the drug to the active site of the enzyme. This infor
mation may reveal how the drug could be modified to yield a second ge-
68 ISSN 0233-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1994. Т. 10, № 6
neration drug for the treatment of the resistant strains of the
pathogen.
This process does not need to await the appearance of resistant stra
ins in the wild. Instead, drug resistant strains can be generated in patho
gens cultured in vitro, under the pressure of low concentrations of the
new drug. The development of resistance to the new drug can be analy
zed as described above and mutations involving the target enzyme can be
identified [41]. By this means, second generation drug can be designed
to treat some of the possible resistant forms of a pathogen, even before
they have occurred in the wild.
Closing. The promises of rational drug discovery/design have long
been debated. However, technological advances have finally brought us
to the point where enzyme structure based drug design can facilitate the
development of new drugs for the treatment of a number of human mala
dies [8, 42—44].
С. Крег
ФЕРМЕНТИ ДОДАТКОВОГО ШЛЯХУ СИНТЕЗУ ПУРИН1В — М>1ШЕНЬ
ДЛЯ ХГМЮТЕРАПЕВТИЧНОГО Л1КУВАННЯ ПАРАЗИТАРНЫХ ХВОРОБ
Р е з ю м е
В отлялх проаналйзовано результаты, як! показують, що досягнення у вивченш специ
фичных молекул-мшеней юптини дозволяють розробляти ефективш лжарсыа засоби
для лжування багатьох захворювань людини. Встановлено, що новий шдх!д до роз,-
робки таких медикаментов базуеться на дослщженш структури молекули фермента.
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Dep. of Biochem. Univ. of Puerto Rico School 08.06.94
of Medicine. San Juan
ISSN 0233-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1994. Т. 10, № 6 71
|
| id | nasplib_isofts_kiev_ua-123456789-155609 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 0233-7657 |
| language | English |
| last_indexed | 2025-12-02T04:57:08Z |
| publishDate | 1994 |
| publisher | Інститут молекулярної біології і генетики НАН України |
| record_format | dspace |
| spelling | Craig, S. 2019-06-17T08:36:35Z 2019-06-17T08:36:35Z 1994 Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases / S. Craig // Биополимеры и клетка. — 1994. — Т. 10, № 6. — С. 65-71. — Бібліогр.: 44 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.0003C5 https://nasplib.isofts.kiev.ua/handle/123456789/155609 616—093/098:577.15 The review analyses the results showing that technological advances in studying the specific target molecules in a cell allow to develop new effective drugs for the treatment of a number of human maladies. The new approach to the drug design is based In the data of enzyme structure. В огляді проаналізовано результати, які показують, що досягнення у вивченні специфічних молекул-мішеней клітини дозволяють розробляти ефективні лікарськи засоби для лікування багатьох захворювань людини. Встановлено, що новий підхід до розробки таких медикаментів базується на дослідженні структури молекули фермента. Обзор анализирует результаты, показывающие, что достижения в изучении специфических молекул-мишеней клетки позволяют разрабатывать эффективные лекарственные средства для лечения многих заболеваний человека. Установлено, что новый подход к разработке таких медикаментов основан на исследовании структуры молекулы фермента. en Інститут молекулярної біології і генетики НАН України Биополимеры и клетка Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases Ферменти додаткового шляху синтезу пуринів – мішень для хіміотерапевтичного лікування паразитарных хвороб Ферменты дополнительного пути синтеза пуринов – мишень для химио- терапевтического лечения паразитарных болезней Article published earlier |
| spellingShingle | Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases Craig, S. |
| title | Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases |
| title_alt | Ферменти додаткового шляху синтезу пуринів – мішень для хіміотерапевтичного лікування паразитарных хвороб Ферменты дополнительного пути синтеза пуринов – мишень для химио- терапевтического лечения паразитарных болезней |
| title_full | Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases |
| title_fullStr | Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases |
| title_full_unstemmed | Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases |
| title_short | Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases |
| title_sort | purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/155609 |
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