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Antimicrobial Agents and Chemotherapy, June 2000, p. 1506-1511, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
In Vitro Activities of Methylenecyclopropane
Analogues of Nucleosides and Their Phosphoralaninate Prodrugs against
Cytomegalovirus and Other Herpesvirus Infections
Rachel J.
Rybak,1
Caroll B.
Hartline,1
Yao-Ling
Qiu,2
Jiri
Zemlicka,2
Emma
Harden,1
Gwen
Marshall,1
Jean-Pierre
Sommadossi,1 and
Earl
R.
Kern1,*
University of Alabama School of Medicine,
Birmingham, Alabama,1 and Barbara Ann
Karmanos Cancer Institute, Wayne State University School of Medicine,
Detroit, Michigan2
Received 16 September 1999/Returned for modification 18 January
2000/Accepted 22 February 2000
 |
ABSTRACT |
Human cytomegalovirus (HCMV) infection does not generally cause
problems in the immunocompetent adult but can result in severe clinical
disease in the fetus, neonate, and immunocompromised host. Ganciclovir
(GCV), the agent currently used to treat most HCMV infections, has
resulted in much therapeutic success; however, efficacy remains
suboptimal. Therefore, there is still a need to develop new compounds
for use against HCMV infections. In the present study, several
Z- and E-series methylenecyclopropane analogues and their phosphoroalaninate prodrugs were tested initially for activity against HCMV, strain AD169, and murine cytomegalovirus (MCMV)
in vitro. Many were found to exhibit efficacy comparable to that of GCV
against HCMV in plaque assays and were active against MCMV as well. The
compounds were also tested for efficacy against herpes simplex virus
types 1 and 2, varicella-zoster virus, and Epstein-Barr virus, and some
had levels of activity that were comparable to that of acyclovir. In
addition, the compounds synguanol (QYL-438) and
2-amino-6-cyclopropylamino analogue (QYL-769) were chosen for further
evaluation and were found to be effective against additional laboratory
and clinical isolates of HCMV and GCV-resistant isolates. QYL-438 and
QYL-769 were found to be nontoxic in human and mouse fibroblasts and
were considerably less toxic than GCV in granulocyte macrophage CFUs
and erythroid burst-forming units. These results provide evidence for
the high activity of some of these methylenecyclopropane analogues
against various herpesviruses, particularly HCMV, in tissue culture and
suggest that further evaluation is warranted to determine their
potential for use in future clinical studies.
| |
INTRODUCTION |
Human cytomegalovirus (HCMV)
infections are the most common cause of congenital viral infections,
occurring in 1 to 2% of all live births (28). This
-herpesvirus is typically benign yet can result in a multitude of
clinical syndromes, particularly in the immunocompromised host (9,
13). Although HCMV infects approximately 40 to 80% of the U.S.
population, the immunocompetent individual rarely manifests overt
symptoms (5, 9, 13). The fetus, neonate, and
immunocompromised patient are most vulnerable to severe disorders, such
as interstitial pneumonia, retardation, hearing loss, microcephaly, and
a mononucleosis-like syndrome, some of which can be fatal (8, 16,
24). Acquired or reactivated virus may occur in up to 80 to 90%
of renal transplant patients, often resulting in devastating disease or
even death (11). The rapid increase in the number of cases
of HCMV infections resulting from organ and bone marrow
transplantation, cancer chemotherapy, and AIDS has prompted a need to
develop more efficacious and less toxic therapeutic agents (1,
22).
Several antiviral compounds have demonstrated efficacy against HCMV,
such as ganciclovir (GCV), foscarnet (PFA), acyclovir (ACV), and
cidofovir (5, 14). GCV has previously demonstrated efficacy
both orally and parenterally in murine cytomegalovirus (MCMV)-infected
mice (4, 8, 10, 12, 25) and has been highly effective in
humans as well. Although the treatment of CMV retinitis,
gastrointestinal disease, and pneumonia is very effective with GCV,
relapses are common once treatment is terminated, and long-term drug
therapy must be sustained in order to maintain antiviral activity
(2, 9). In addition, neutropenia and thrombocytopenia may
occur as major side effects, and resistant isolates may develop as well
(3, 14, 15).
The recent development of nucleoside analogues with a Z- or
E-methylenecyclopropane moiety has led to the evaluation of
these compounds as possible antiviral agents. As reported previously, the replacement of the ribofuranose moiety of unsaturated acyclic nucleoside analogues by a rigid allenic residue (adenallene and cytallene) has demonstrated significant anti-human immunodeficiency virus efficacy (6). This development led to the synthesis of a new group of compounds which possess a methylenecyclopropane system
substitution in place of the allenic residue. In addition, lipophilic
phosphate prodrugs of methylenecyclopropane analogues have exhibited
antiviral activity in past studies (21, 23, 29). Thus,
compounds with potent antiviral activity against a broader range of
viruses, such as several of the herpesviruses, were developed. Many of
these nucleoside analogues have been evaluated for antiviral activity
and have demonstrated in vitro and in vivo activities against HCMV and
MCMV as previously reported (18, 20, 23).
The purpose of the following studies was to further evaluate the
antiviral activity of several methylenecyclopropane analogues and
phosphoroalaninate prodrugs for their efficacy against various herpesviruses, particularly the cytomegaloviruses, in vitro. The compounds were compared to GCV against HCMV and MCMV, and to ACV against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2,
respectively), varicella-zoster virus (VZV), and Epstein-Barr virus
(EBV). In addition, all compounds were evaluated for cellular toxicity
in fibroblast, lymphoblastic, or bone marrow precursor cells.
| |
MATERIALS AND METHODS |
Media and virus strains.
The medium utilized was Earle's
minimal essential medium (MEM) (Mediatech, Inc., Herndon, Va.)
containing Earle's balanced salt solution supplemented with either 2 or 10% fetal bovine serum, 100 U of penicillin per ml, 25 µg of
gentamicin per ml, and 2 mM L-glutamine.
The HCMV strain used for determining activity initially was AD169.
Additional clinical and GCV-resistant HCMV strains were provided by
Karen Biron of Glaxo Wellcome (Research Triangle Park, N.C.). The
GCV-resistant isolates all were UL97 mutants except 759RD100, which had a mutation in UL97 and in the DNA
polymerase. Virus strain E-377 was utilized for HSV-1, and strain MS
was utilized for HSV-2. The strains used for EBV and VZV were P3HR-1
and Ellen, respectively.
Cell cultures.
Human foreskins were obtained from the
University of Alabama at Birmingham Hospital and the human foreskin
fibroblasts (HFF) were prepared for use in the HCMV, HSV-1, HSV-2, and
VZV assays and for cytotoxicity and cell proliferation assays
(7). Mouse embryo fibroblasts (MEF) were prepared from mouse
embryos (age, 14 to 16 days) as reported previously (7)
for use in MCMV assays. Daudi cells were used in assays to
determine drug efficacy against EBV and in lymphoblastic cell
proliferation assays for toxicity. Granulocyte macrophage CFU (CFU-GM)
and erythroid burst-forming units (BFU-E) were used for bone marrow
progenitor cell toxicity evaluation (26).
Antiviral drugs.
The methylenecyclopropane analogues and
prodrugs evaluated were as follows: QYL-284A (synadenol), QYL-788
[S-(+)-synadenol], QYL-587A
[R-(
)-synadenol], QYL-468 (syncytol), QYL-438
(synguanol), QYL-678 (prodrug of synguanol), QYL-769
(2-amino-6-cyclopropylamino analogue), QYL-975 (prodrug of
2-amino-6-cyclopropylamino analogue), QYL-546 (2,6-diaminopurine
analogue), QYL-685 (prodrug of 2,6-diaminopurine analogue), QYL-418
(2-amino-6-chloropurine analogue), QYL-941 (2-amino-6-methoxypurine
analogue), and QYL-972 (prodrug of 2-amino-6-methoxypurine analogue).
The synthesis of these compounds was described previously (18, 19,
20, 21) and the structures are presented in Fig. 1 and 2.
The compounds were prepared in dimethyl sulfoxide (DMSO) at 10 mg/ml
and diluted 1:10 in MEM containing 2% FBS to reach a final stock
concentration of 1000 µg/ml. GCV and ACV were purchased from the
University of Alabama at Birmingham Hospital Pharmacy and were prepared
in sterile water.
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FIG. 2.
Structures of the lipophilic phosphate prodrugs of the
methylenecyclopropane analogues of nucleosides.
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Antiviral assays for drug evaluation.
The efficacy of these
nucleoside analogues against HCMV, MCMV, HSV-1, and HSV-2 was
determined by cytopathic effect (CPE) inhibition and plaque reduction
(PR) assays, as reported previously (19). VZV was tested in
plaque reduction assays only. Efficacy of the analogues against EBV was
determined using viral capsid antigen (VCA) expression in P3HR-1 Daudi
cells by immunofluorescence and a DNA hybridization assay as reported
previously (18). Inhibition of DNA synthesis was determined
utilizing the Enzo Simply Sensitive Horseradish Peroxidase-AEC In Situ
Detection System for EBV (Enzo Diagnostics, Farmingdale, N.Y.).
The toxicities of the compounds in HFF and MEF were determined by
neutral red uptake and cell proliferation assays in HFF
as described
previously (
18). QYL-438 and QYL-769 were further
evaluated
for toxicity in human lymphoblastic and bone marrow
progenitor cells as
described previously (
26,
27). The MacSynergy
II, version
1.0 (University of Michigan, 1992 release), computer
program was used
to calculate the 50% effective concentration
(EC
50), 50%
cytotoxic concentration (CC
50), and 50% inhibitory
concentration (IC
50). In general, these assays were
performed
only once due to a limited drug supply. However, in selected
cases,
two assays were performed, and in these cases the means and
standard
deviations are
included.
| |
RESULTS |
Antiviral efficacy of the methylenecyclopropane analogues.
Thirteen methylenecyclopropane analogues and prodrugs demonstrated
moderate or good activities against HCMV in both CPE inhibition and PR
assays (Table 1). QYL-438 was the most
potent compound and exhibited EC50 values of 0.04 and 1.2 µM in the CPE inhibition and PR assays, respectively. This was
comparable to or better than GCV, which showed EC50 values
of 0.39 and 2.3 µM for the corresponding assays. Good antiviral
activity of the 13 compounds was also demonstrated against MCMV in
plaque reduction assays, with QYL-438 (EC50 = 0.30 µM) and QYL-418 (EC50 = 0.27 µM) being the most
potent compounds compared to GCV (EC50 = 2.0 µM).
Several other compounds were highly efficacious as well, with
EC50 values of <2.0 µM. In addition, most compounds were
only moderately toxic or nontoxic in MEF as determined by visual
inspection (CC50 of 100 to >500 µM) compared to GCV
(CC50 >39.2 µM).
The excellent antiviral activity and low toxicity of QYL-438, as well
as those of QYL-769, led to their selection for further
evaluation
against additional laboratory and clinical HCMV strains,
and both were
as active as or more active than GCV (Table
2),
with EC
50 values ranging
from 1.2 to 11.6 µM for QYL-438 and 2.2
to 10.6 µM for QYL-769,
compared to GCV (EC
50 of 2.3 to 9.8 µM).
In addition,
QYL-438 and QYL-769 demonstrated activities against
all the
GCV-resistant HCMV isolates tested (Table
3). QYL-769
was particularly active with
a 5- to 10-fold or greater efficacy
compared to GCV for most of the
resistant strains tested.
The methylenecyclopropane analogues were also evaluated against HSV-1
and HSV-2, and the results indicated excellent activities
of four of
the drugs tested in plaque reduction and CPE inhibition
assays compared
to ACV (Table
4). All four compounds had
similar
activities against HSV-2 in both CPE inhibition and PR assays.
Several analogues were tested against VZV in PR assays, and most
exhibited activity that was comparable to that of ACV, as
shown in
Table
5. The analogues were next
evaluated for activity
against EBV using VCA and DNA hybridization
assays (Table
6).
Most compounds were
found to be highly active, generally similar
to or better than ACV. In
addition, QYL-438 and QYL-769 were further
evaluated against EBV in a
DNA synthesis reduction assay, and
both were comparable to ACV.
Toxicity results in Daudi cells indicated
that most of the analogues
were similar to ACV.
Neutral red uptake and cell proliferation assays were performed to
further evaluate the cellular cytotoxicity and inhibition
of cell
growth of the 13 analogues in HFF (Table
7). Several
compounds were nontoxic and
similar to GCV or ACV (CC
50 > 392
µM), while some
exhibited slight to moderate levels of toxicity.
QYL-438 and QYL-769
were chosen for further evaluation in human
lymphoblastic and bone
marrow progenitor cells (Table
8). Both
QYL-438 (IC
50 = 12.9 µM) and QYL-769
(IC
50 = 27.9 µM) were more
toxic than GCV
(IC
50 > 196 µM) in cell proliferation assays in
Daudi cells but were slightly less toxic than GCV in HFF. They
were
significantly less toxic, however, than GCV in CFU-GM and
BFU-E bone
marrow assays.
| |
DISCUSSION |
Infection with HCMV has the potential to produce life-threatening
clinical syndromes in the immunocompromised patient. Effective therapeutic agents, such as GCV, PFA, and cidofovir, have been utilized
to combat the manifestations of these infections; however, the
occurrence of resistant strains and adverse side effects has limited
their use. Therefore, it is necessary to continue the search for novel
compounds for the treatment of CMV as well as other herpesvirus infections.
The search for new nucleoside analogues for antiviral therapy has led
to the synthesis of many potent compounds. Unsaturated acyclic
nucleoside analogues possessing a rigid allenic residue (adenallene and
cytallene) in place of a ribofuranose moiety have previously been shown
to exhibit strong activity against human immunodeficiency virus
(6). Thus, the replacement of a double bond in the allenic
residues with a cyclopropane ring widely expanded the range of efficacy
of these compounds (18, 20). This structural modification
served as the motivation for the development of novel compounds with a
methylenecyclopropane moiety in place of an allenic group (18, 20,
23). In addition, it has been previously reported that many
lipophilic phosphate prodrugs of methylenecyclopropane analogues have
demonstrated antiviral activity and have been investigated in vitro and
in vivo (23, 29). As reported previously, compounds QYL-769
and QYL-438 have been evaluated against HCMV and several nonhuman CMVs,
such as rat CMV, MCMV, guinea pig CMV, and rhesus monkey CMV
(24). The results indicated that QYL-769 and QYL-438 had
excellent activity against MCMV, rat CMV, and rhesus monkey CMV
compared to GCV. Additionally, QYL-769 was very active against guinea
pig CMV compared to GCV. QYL-284A, QYL-438, QYL-941, QYL-972, and
QYL-769 were also evaluated in MCMV-infected mice, and all demonstrated
significant activity when delivered orally, particularly QYL-769, which
had activity similar to that of GCV (23).
The present study investigated 13 of the methylenecyclopropane
analogues and prodrugs in vitro, and all were found to be active against HCMV and MCMV in CPE inhibition and PR assays, with activity similar to or better than that of GCV. Particularly potent was QYL-438
against HCMV, and QYL-418 and QYL-438 were particularly potent against
MCMV. QYL-438 and QYL-769 were further evaluated against additional
HCMV strains, and both agents were found to have activities similar to
GCV against laboratory and clinical isolates and all were highly
effective against GCV-resistant strains as well.
The methylenecyclopropane analogues were further tested against other
herpesviruses in addition to CMV to determine their potential as
therapeutic agents against these opportunistic viruses. Intravenous ACV
is currently utilized for treatment of both HSV-1 encephalitis and
HSV-2 genital disease and is highly effective (11). However,
the lack of effective topical activity for herpes labialis or herpes
genitalis indicates the need for agents effective against these
diseases as well. The results of the present study indicated that some
of the analogues had activity against HSV-1 and HSV-2 that was as good
as that of ACV. In addition, several of the analogues were evaluated
against EBV, and most were highly active, particularly QYL-438 and
QYL-769, which were similar to or more active than ACV.
Cellular toxicity is a crucial factor in determination of a compound's
potential as an antiviral agent in addition to efficacy. Neutral red
uptake and cell proliferation assays in HFF indicated moderate or no
toxicity of most of the compounds compared to GCV and ACV. In MEF, most
compounds were nontoxic or moderately toxic compared to GCV. QYL-438
and QYL-769 were also evaluated for toxicity in clonogenic assays
utilizing bone marrow progenitor cells. In this study, both analogues
were less toxic than GCV in CFU-GM and BFU-E assays. In previous
studies, the CFU-GM and BFU-E assay system has been shown to be
appropriate for the determination of possible hematotoxicity and thus
is considered a more sensitive assay for determining systemic or bone
marrow toxicity than tissue culture cells (17, 24).
These results support the potential use of several of the
methylenecyclopropane analogues and their prodrugs as antiviral agents.
The tissue culture data provide convincing evidence for the excellent
activities of many of these compounds, and some have been shown to have
activity against MCMV in vivo (23). The efficacy and
toxicity were comparable to or better than those of GCV or ACV for
several of the analogues, thus suggesting the need for future
evaluation of these and similar compounds.
| |
ACKNOWLEDGMENTS |
This work was supported by contracts N01-A1-35177 and
N01-A1-65290 from The Antiviral Substance Program, NIAID, NIH, and
research grant R01-CA32779 from the NCI, NIH.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: UAB-Dept. of
Pediatrics, BBRB 309, 1530 3rd Ave. S., Birmingham, AL 35294-2170. Phone: (205) 934-1990. Fax: (205) 975-1992. E-mail:
Kern{at}uab.edu.
| |
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Antimicrobial Agents and Chemotherapy, June 2000, p. 1506-1511, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
