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PubMed1993

Enhancement of allograft survival by combination RS-61443 and DUP-785 therapy.

Current maintenance immunosuppressive therapy consists of cyclosporine in combination with prednisone and azathioprine. Unfortunately these agents are associated with significant side effects resulting in post-transplant morbidity and mortality. Therefore, the search for new immunosuppressive agents is essential, not only to improve the results after organ transplantation but equally important to reduce morbidity. Recently two new antiproliferative drugs, RS-61443 (RS) and DUP-785 (DUP), have become available. RS (mycophenolate mefotil), a semisynthetic derivative of mycophenolic acid, inhibits purine de novo synthesis by noncompetitively and reversibly inhibiting inosine monophosphate dehydrogenase. DUP (brequinar sodium) inhibits pyrimidine synthesis by reversibly inhibiting dehydroorotate dehydrogenase. We evaluated subtherapeutic combination RS and DUP therapy in the rat (ACI-->LEW) heterotopic heart allograft model. Median graft survival with no treatment, RS (20 mg/kg/day), DUP 3 mg/kg (3x /week), or DUP 6 mg/kg (3x/week) was 6.5, 11.5, 9.5 and 14.5, respectively. Median graft survival with combination therapy (RS 20 mg/kg, DUP 6 or 3 mg/kg 3x/week) was 133 days and 121 days, respectively. Furthermore, mean survival following cessation of all therapy at 100 days posttransplant was dramatically prolonged to 65.7 +/- 43.8 days in animals receiving combination therapy (RS 20 mg/kg/day, DUP 6 mg/kg 3x/week). Despite the potent immunosuppressive activity, recipients treated with combination therapy demonstrated no side effects and gained body weight during the treatment. To determine if low-dose combination therapy was effective in reversing ongoing rejection, treatment was delayed until the 5th postoperative day. Four of 5 recipients (80%) receiving RS monotherapy (60 mg/kg/day), 5 of 5 recipients (100%) receiving DUP monotherapy (12 mg/kg/day), and 4 of 5 grafts (80%) receiving combination therapy (RS 40 mg/kg/day and DUP 6 mg/kg/day) survived over 21 days. Our results demonstrated that combination therapy significantly prolonged graft survival, and that the progression of advanced rejection was halted immediately. RS and DUP combination may provide a potent immunosuppressive therapy in clinical transplantation.

Animals↗
PubMed1993

Hamster-to-rat heart and liver xenotransplantation with FK506 plus antiproliferative drugs.

Heterotopic hamster hearts transplanted to unmodified LEW rats underwent humoral rejection in 3 days. Survival was prolonged to a median of 4 days with 2 mg/kg/day FK506. As monotherapy, 15 mg/kg/day cyclophosphamide greatly prolonged graft survival--far more than could be accomplished with RS-61443, brequinar (BQR), mizoribine, methotrexate, or deoxyspergualin. However, when FK506 treatment, which was ineffective alone, was combined with a short induction course (14 or 30 days) of subtherapeutic BQR, RS-61443, or cyclophosphamide, routine survival of heart xenografts was possible for as long as the daily FK506 was continued. In addition, a single large dose of 80 mg/kg cyclophosphamide 10 days preoperatively allowed routine cardiac xenograft survival under FK506. The ability of these antimetabolites to unmask the therapeutic potential of FK506 correlated, although imperfectly, with the prevention of rises of preformed heterospecific cytotoxic antibodies immediately postoperatively. As an adjunct to FK506, azathioprine was of marginal value, whereas mizoribine, methotrexate, and deoxyspergualin (DSPG) were of intermediate efficacy. After orthotopic hepatic xenotransplantation, the perioperative survival of the liver with its well-known resistance to antibodies was less dependent than the heart on the antimetabolite component of the combined drug therapy, but the unsatisfactory results with monotherapy of FK506, BQR, RS-61443, or cyclophosphamide were changed to routine success by combining continuous FK506 with a short course of any of the other drugs. Thus, by breaking down the antibody barrier to xenotransplantation with these so-called antiproliferative drugs, it has been possible with FK506 to transplant heart and liver xenografts with consistent long-term survival of healthy recipients.

Animals↗
PubMed1993

The synergistic interactions in vitro and in vivo of brequinar sodium with cyclosporine or rapamycin alone and in triple combination.

The rigorous median-effect analysis was used to assess the interactions between cyclosporine and drugs that inhibit nucleotide synthesis pathways. Using in vitro proliferation assays wherein human lymphocytes were triggered by phytohemagglutin, anti-CD3 monoclonal antibody, or mixed lymphocyte reactions, CsA was shown to display additive interactions with 6-mercaptopurine (6-MP), mizorbine (MZB), and mycophenolic acid (MPA), and a synergistic interaction with brequinar (BQR). In the in vitro assays, BQR contributed a further synergistic effect to the double-drug combination CsA/rapamycin (RAPA). Of the four inhibitors of nucleotide synthesis pathways, only BQR noncompetitively inhibited IL-2-stimulated proliferation of the CTLL-2 cell line. Using the in vivo assay of heterotopic Buffalo (BUF, RT-1b) cardiac allografts in Wistar-Furth (WFu, RT-1u) hosts, oral administration of BQR displayed about 100% bioavailability--which, like the bolus intravenous (i.v.) mode, was eight-fold more effective than continuous i.v. infusions. Furthermore median-effect analysis of serial amounts of orally administered BQR demonstrated that it contributes synergistically to the immunosuppressive effects of intravenously delivered CsA/RAPA (0.5/0.01 mg/kg/day). The degree of synergism was proportionate to the extent of the immunosuppression. These findings document the potency of the CsA/RAPA/BQR triple-drug combination and suggest that the synergistic effects may permit dose reductions of each component, thereby mitigating toxicities resulting from the large amounts of individual agents necessary to achieve allo-unresponsiveness.

Antibodies↗
PubMed1993

The antilymphocytic activity of brequinar sodium and its potentiation by cytidine. Effects on lymphocyte proliferation and cytokine production.

Based on its capacity to inhibit de novo pyrimidine biosynthesis by blocking dihydroorotate dehydrogenase activity, the antitumor agent brequinar sodium (BQR) has emerged as a new immunosuppressive agent. Since BQR is known to prevent the synthesis of nucleotides during cell proliferation, we hypothesized that it would be highly effective in controlling strong lymphocyte proliferative responses but might be less effective in controlling comparatively weak responses that do not necessarily involve new nucleotide synthesis. We addressed this question by culturing murine spleen cells with different types of stimuli, including Con A, phorbol myristate acetate +/- ionomycin, anti-CD3, and anti-Igs. Addition of BQR (0.001 microgram/ml to 10 micrograms/ml) at the start of a 72-hr culture period caused dose-dependent inhibition of strong proliferative responses, induced either by Con A (5 micrograms/ml) or PMA+ionomycin. A residual degree of proliferation persisted, however, even at the highest BQR concentrations. In contrast, no impairment of low-concentration Con A (0.5 or 0.1 microgram/ml), anti-CD3, or anti-Igs responses was observed. In order to ascertain its role in arresting nucleotide synthesis, we attempted to reverse the inhibitory effect of BQR by adding exogenous uridine or cytidine to lymphocyte cultures. BQR's inhibitory activity was reversed completely by adding uridine at 0.1 mM. In contrast, combination of BQR and cytidine (0.1 mM) potentiated BQR's activity and abrogated anti-CD3 or anti-Igs-induced lymphocyte proliferation in a dose-dependent manner. A synergistic inhibitory action between BQR and cytidine was observed when the BQR concentration was higher than 0.1 microgram/ml and with cytidine at 0.1 mM. Production of interleukin-2 and IL-4 was only slightly affected by BQR, but was significantly suppressed by coadministration of BQR and cytidine. Neither BQR (5 micrograms/ml) on its own, however, nor combination of BQR with cytidine affected production of mRNA for IL-2, IL-4, or interferon-gamma, as determined by reverse-transcription polymerase chain reaction. Our observations suggest that BQR may not only affect dihydroorotate dehydrogenase activity, but may also inhibit the enzyme cytidine deaminase, which converts cytidine to uridine. These antimetabolic effects of BQR complement the well-known cytokine synthesis inhibitory actions of FK506 or CsA. The combination of BQR and cytidine, however, offers a further possibility for inhibition of both cytokine production and T and B cell proliferation, and may have potential for the control of graft rejection.

Animals↗
PubMed1993

The synergism of brequinar sodium and cyclosporine used in combination to prevent cardiac allograft rejection in the rat.

Brequinar sodium (BQR) is a novel immunosuppressive drug that inhibits cell proliferation by virtue of its disruption of the de novo pyrimidine biosynthesis. The basis of the immunosuppressive activity of BQR is distinctively different from that of cyclosporine (CsA), and we have recently evaluated in vivo and in vitro the efficacy of the two drugs when used in combination. Subtherapeutic doses of BQR and CsA were tested for their ability to prolong heterotopic cardiac allograft survival in the MHC- and non-MHC-mismatched ACI-->LEW rat strain combination. The graft survival data derived from these experiments were analyzed using the median-effect analysis to establish the immunosuppressive interaction of both drugs. The administration of BQR 3 mg/kg three times weekly or CsA 2.5 mg/kg daily moderately prolonged cardiac allograft survival, with a mean survival of 10 +/- 0.5 and 16 +/- 5.3 days, respectively. The use of the two drugs in combination with the same dose schedule exerted a synergistic effect on graft survival, prolonging the graft function to a mean of 31 +/- 5.7 days. Sera from animals treated with the two drugs displayed, when compared with single treatment groups (BQR 3 mg/kg and CsA 2.5 mg/kg), significantly (P < 0.01) increased in vitro inhibition of lymphocyte proliferation following stimulation with PHA. Finally, a clear correlation between the mean survival time and BQR plasma levels of animals treated with BQR alone or in combination with CsA was seen. Those treatment groups with BQR levels below 2 micrograms/ml (1.5 and 3.0 mg/kg/3x/week) had a mean graft survival of less than 10 days). In contrast, recipients treated with a combination of low doses of BQR and CsA displayed higher drug plasma levels (> 2 micrograms/ml) and longer mean graft survival times. These observations suggest that BQR and CsA may be highly effective when used in combination to prevent organ allograft rejection for clinical transplantation.

Animals↗
PubMed1993

The prevention of accelerated cardiac allograft rejection in sensitized recipients after treatment with brequinar sodium.

Brequinar sodium (BQR) is a novel immunosuppressive agent that is highly effective in preventing B lymphocyte-mediated antibody production. We have examined the effects of BQR treatment in sensitized recipients on graft survival, donor-specific antibody responses (IgM and IgG), and the appearance of immunopathological lesions present in the grafts. LEW rat recipients were sensitized with single ACI skin graft on day 7 and received heterotopic ACI cardiac grafts on day 0. The recipients rejected the cardiac grafts in an accelerated fashion at day 2.5 post-transplantation, compared to day 7.0 in unsensitized recipients. The animals were treated with low (3 mg/kg/day) or high (12 mg/kg/3x weekly) doses of BQR during skin graft sensitization and/or after challenge with ACI heart allografts. All groups treated with BQR showed significant prolongation of graft survival in the sensitized recipients. The best survival was observed following high-dose BQR therapy during both sensitization and effector phases (median survival time = 40.0 days, P << 0.001). Daily treatment with BQR (3 mg/kg/day) prevented IgM (but not IgG) antibody responses. Treatment with higher doses of BQR (12 mg/kg/3x weekly) before and after skin graft sensitization was effective in preventing both IgM and IgG production. In general, BQR treatment resulted in effective suppression of anti-donor antibody responses, stable graft function, and a reduction in the severity of the acute vascular lesions in the graft. The effectiveness of BQR in preventing accelerated graft rejection when used at 12 mg/kg/3x weekly was comparable to that seen with treatment of sensitized animals with CsA at 15 mg/kg/day for 30 days. Daily treatment with cyclophosphamide at 5 or 15 mg/kg/day was ineffective for preventing graft rejection in sensitized recipients. These results indicated that BQR may provide an important addition to treatment protocols designed to prevent transplantation rejection in presensitized patients. BQR has the ability to significantly inhibit host cellular and humoral immune responses to the donor graft and this facet of the immunosuppressive activity of the drug may be responsible for preventing this aggressive form of rejection.

Animals↗
PubMed1994

Evaluation of cyclosporine, mycophenolate mofetil, and Brequinar sodium combination therapy on hamster-to-rat cardiac xenotransplantation.

We examined the effect of CsA, mycophenolate mofetil (MM), and Brequinar sodium (BQR) combination therapy on hamster-to-rat cardiac xenotransplantation survival. Since the mechanism of rejection in concordant cardiac xenotransplantation may be antibody mediated as well as cellularly (CD4) mediated, we also examined the effect of these agents on antidonor antibody levels. In untreated controls, rejection occurred within 4 days, with elevation of cytotoxic antibody titers and severe humoral destruction of the xenografted hearts. It involved both IgM and IgG antibody-mediated humoral immunity. CsA alone (20 mg/kg/day) could not modify this pattern of rejection. High-dose MM (40/20 mg/kg/day)+BQR (12/6 mg/kg 3 times a week) combination therapy achieved slight prolongation of survival and suppressed the elevation of cytotoxic antibody titers relative to controls. While these grafts were rejected within 2 weeks, humoral destruction in the rejected xenografts and antibody deposition were reduced. Combination of CsA (20 mg/kg/day) with BQR (3 or 12 ng 3 times/week) dramatically increased graft survival. When CsA (20 mg/kg/day) was combined with MM (20 mg/kg/day) and BQR (3 mg/kg/day), xenograft survival was significantly prolonged (P < 0.002); however, significant toxicity was observed. Cytotoxic antibody formation was delayed for 1 month in most cases. Histological examination revealed cellular rejection with little evidence of humoral rejection. Thus, combination therapy consisting of CsA and BQR or CsA, MM, and BQR was effective in delaying the rejection of hamster-to-LEW rat concordant cardiac xenografts. The mechanism of prolonged graft survival may involve delayed humoral response and prevention of the cellular response.

Animals↗
PubMed1994

Novel mechanisms of brequinar sodium immunosuppression on T cell activation.

Brequinar sodium (BQR) is a novel immunosuppressive agent that acts by inhibiting the activity of dihydroorotate dehydrogenase, the fourth enzyme in the de novo pyrimidine biosynthetic pathway. The activity of BQR as an immunosuppressive agent is believed to be inhibition of antigen-induced lymphocyte proliferation through inhibition of DNA and RNA synthesis. BQR, therefore, has a different mechanism of action than cyclosporine and may potentiate the immunosuppressive effects of cyclosporine. In this study, we determined the effect of BQR on peripheral blood mononuclear cell (PBMC) activation in a series of in vitro culture systems. In these studies, BQR inhibited PHA-stimulated activation in a dose-dependent fashion beginning at 10(-6) M. The immunosuppressive effect of BQR was similar in magnitude to cyclosporine. Proliferation assays suggested an additive immunosuppression by the combination of BQR and cyclosporine. Similar inhibition of CD2-stimulated or CD3-stimulated activation of PBMC was found. The mechanisms of action of BQR were complex. BQR inhibited interleukin 2 protein production in response to mitogen stimulation. Cell surface interleukin 2 receptor expression was inhibited by BQR. BQR inhibited cell cycle progression, preventing progression from G0/G1 into S and G2 + M phases. BQR had no effect on induction of transcripts for the interleukin 2 receptor, but markedly inhibited the production of transcripts for interleukin 2. Thus, our studies indicate that BQR exerts a potent immunosuppression on mitogen-induced PBMC activation through multiple mechanisms. Consequently, BQR may be an effective agent for immunosuppression in organ transplantation or inflammatory diseases.

Biphenyl Compounds↗
PubMed1996

Beneficial effect of graft perfusion with anti-T cell receptor monoclonal antibodies on survival of small bowel allografts in rat recipients treated with brequinar alone or in combination with cyclosporine and sirolimus.

In the present experiments, a multimodality regimen was developed that included an anti-T cell receptor R73 monoclonal antibody and the pharmacologic agents brequinar (BQR), cyclosporine (CsA), and sirolimus (rapamycin; RAPA) to prolong the survival of small bowel (SB) allografts. BQR was the most potent single drug: the 4.0 or 8.0 mg/kg/day BQR doses delivered every second day (q.o.d.) per gavage for 28 days prolonged the survival of Brown Norway (BN; RT1n) SB allografts in Lewis (LEW; RT1l) recipients from a mean survival time of 10.6 +/- 1.9 days in untreated controls to 29.2 +/- 5.8 days, respectively (both P < 0.001). When treatment was extended to 56 days, 8.0 mg/kg/q.o.d BQR produced a mean survival time of 83.8 +/0 33.8 days (P < 0.001), with 2/5 hosts surviving more than 100 days. In a host-versus-graft model, BQR (8.0 mg/kg/q.o.d) delivered for 28 days with CsA (2.0 mg/kg/day) and RAPA (0.04 mg/kg/day) delivered intravenously for 14 days prolonged the survival of BN SB grafts in LEW recipients to 54.4 +/- 21.0 days (P < 0.001). Extending triple-drug therapy to 42 days induced the prolongation of SB allograft survival to greater than 100 days in 5/7 recipients. Although pretransplant perfusion of the grafts with R73 mAb was ineffective alone, the combination of graft perfusion and a 28-day course of BQR (8.0 mg/kg/q.o.d) in the GVH model indefinitely prolonged LEW graft in F1 recipients. Alternatively, indefinite survival of SB allografts ( > 100 days; P < 0.001) was achieved by the combination of a 14-day course of a triple-drug regimen using each agent at subtherapeutic doses, namely BQR (2.0 mg/kg/q.o.d.), CsA (2.0 mg/kg/day), and RAPA (0.04 mg/kg/day). The state of transplantation tolerance is these hosts was documented by the acceptance of donor-type but not third-party heart allografts.

Animals↗
PubMed1996

The significance of timing of additional short-term immunosuppression in the donor-specific transfusion/cyclosporine-treated rat.

It is hypothesized that the mechanism, or mechanisms, responsible for donor-specific transfusion (DST)/cyclosporine (CsA) immunosuppression is generated by an active immune response that is most dynamic in the immediate peritransplant period and thus might be at the peak of vulnerability to the influences of added immunosuppression. To better define this concept, four immunosuppressive drugs were combined with a d-1 DST and 14-day course of CsA in the ACl-to-Lewis cardiac transplant model. A 5-day course of antithymocyte globulin (ATG) initiated at d-1 or d+4 with DST/CsA reduced survival vs. DST/CsA alone (27.0 +/- 2.6 days and 24.6 +/- 5.7 days vs. 95.3 +/- 16.3 days, P<.05). Delay of initiation to d+7 improved survival to 39.5 +/- 8.9 days. A 5-day course of methylprednisolone (MP) begun at d-1 with DST/CsA decreased survival vs. DST/CsA alone, 59.2 +/- l0.0 days vs. 95.3 +/- 16.3 days, but delay to d+4 improved survival to 110 +/- l8 days, P<.05 vs d-1. A 3-day course of brequinar (Breq) begun at d-1 with DST/CsA increased survival to 244 +/- 48.6 days, while delay to d+4 reduced survival to 49.0 +/- 6.7 days, P<.05 vs. d-1. Finally, a 5-day course of rapamycin (Rapa), was given with d-1 DST/CsA treatment beginning on d-1, d0, d+l, d+3, d+5, and d+7. In this instance, no significant differences in survival were found between timing groups or DST/CsA control. Together, these data support the hypothesis that DST/CsA treatment generates an active immune response that is inhibited by early initiation of ATG or MP, enhanced by early administration of Breq, and unchanged by early administration of Rapa.

Animals↗
PubMed2004

Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain.

The flavin enzyme dihydroorotate dehydrogenase (DHOD; EC 1.3.99.11) catalyzes the oxidation of dihydroorotate to orotate, the fourth step in the de novo pyrimidine biosynthesis of UMP. The enzyme is a promising target for drug design in different biological and clinical applications for cancer and arthritis. The first crystal structure of the class 2 dihydroorotate dehydrogenase from rat has been determined in complex with its two inhibitors brequinar and atovaquone. These inhibitors have shown promising results as anti-proliferative, immunosuppressive, and antiparasitic agents. A unique feature of the class 2 DHODs is their N-terminal extension, which folds into a separate domain comprising two alpha-helices. This domain serves as the binding site for the two inhibitors and the respiratory quinones acting as the second substrate for the class 2 DHODs. The orientation of the first N-terminal helix is very different in the two complexes of rat DHOD (DHODR). Binding of atovaquone causes a 12 A movement of the first residue in the first alpha-helix. Based on the information from the two structures of DHODR, a model for binding of the quinone and the residues important for the interactions could be defined. His 56 and Arg 136, which are fully conserved in all class 2 DHODs, seem to play a key role in the interaction with the electron acceptor. The differences between the membrane-bound rat DHOD and membrane-associated class 2 DHODs exemplified by the Escherichia coli DHOD has been investigated by GRID computations of the hydrophobic probes predicted to interact with the membrane.

Amino Acid Sequence↗
PubMed1998

Demonstration of multilineage chimerism in a nonhuman primate concordant xenograft model.

Prior studies from our laboratory have demonstrated that a nonmyeloablative conditioning regimen can induce transient mixed chimerism and renal allograft tolerance between MHC disparate cynomolgus monkeys. We have also shown that this preparative regimen can be extended to a concordant baboon to cynomolgus xenograft model by adding, to the post transplant protocol, therapy designed to prevent antibody production. Here we examine the use of brequinar (BQR) for this purpose and the efficacy of two new reagents developed to demonstrate the establishment of chimerism in the xenograft recipients. The cynomolgus recipients were conditioned with WBI (300 cGy), TI (700 cGy), ATG, cyclosporine, and brequinar sodium. To detect engraftment of the donor marrow, we prepared a polyclonal cynomolgus anti-baboon antibody (CABA) and a monoclonal antibody (215.1), which distinguish baboon and cynomolgus lymphocytes and granulocytes. We employed flow cytometry analysis to detect multilineage chimerism in the xenograft recipients. Five of the six recipients monitored using our new reagents (CABA and 215.1) developed detectable chimerism and only one of these animals lost its kidney to rejection. However, other complications have not permitted assessment of long-term outcome. The features of the multilineage chimerism included the detection of donor granulocytes (1.8-77.4%) and lymphocytes (2.4-22.2%) for 9 to 37 days. Our new reagents permit the detection of multilineage mixed chimerism, which may be a predictor of xenograft tolerance. We also conclude that brequinar may be effective in preventing antibody formation, but because of its toxicity, it is probably not the drug of choice for extension of the mixed chimerism protocol to concordant xenografts.

Animals↗
PubMed1993

The development of Brequinar as an immunosuppressive drug for transplantation.

The preclinical and clinical characterization of Brequinar sodium has demonstrated the potential for the use of this drug as a component of a polytherapeutic treatment strategy to prevent the rejection of organ grafts. Brequinar, along with several other new immunosuppressive drugs, including Mizorbine, 15-deoxyspergualin, and Mycophenolate mofetil, is an antimetabolite with immunosuppressive activity and toxic side effects that are distinctly different from those of CsA and the newly characterized FK 506. This combination of effective antiproliferative activity exhibited by these newer agents and the well-established effect of CsA on T-lymphocyte activation offers the potential for the development of immunosuppressive regimens that are significantly more effective with fewer side effects for the patient. The concept of synergistic interaction between these two classes of immunosuppressive agents has been tested experimentally and found to be extremely effective for both allograft and xenograft models of graft rejection (Cosenza et al. 1993, 1993a, Stepkowski & Kahan 1993). It remains to be established that a similar synergism will exist for clinical transplantation. The effectiveness of CsA as a primary immunosuppressive agent, however, assures the inclusion of CsA in any polytherapeutic approach to be tested in the near future. New clinical trials designed to prove efficacy for immunosuppressive agents, such as BQR, will use CsA or FK 506 as a primary component of the treatment protocol. The combination of immunosuppressive agents that will eventually be applied in wide clinical use is not clear. While some new immunosuppressive agents have been more extensively tested clinically, BQR exhibits a number of unique features that make this compound particularly attractive for inclusion in new immunosuppressive regimens. The drug is readily soluble in aqueous solutions and can be administered intravenously or orally with equal effectiveness. Brequinar exhibits a high level of bioavailability following oral administration and an extended half-life that permits less frequent administration. While the metabolic byproducts of BQR have not been clearly described, there is good evidence that the parent compound exhibits the majority, if not all, of the immunosuppressive activity. The ability to monitor the parent drug directly or measure the depletion of enzyme products that reflect the activity of the drug are important features of the drug that simplify its use in a clinical setting. Although BQR exhibits important adverse side effects at high doses, the effects of the drug are characteristic of antimetabolites and are therefore predictable, constant, and reversible.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Biochemical characterization of recombinant dihydroorotate dehydrogenase from the opportunistic pathogenic yeast Candida albicans.

Candida albicans is the most prevalent yeast pathogen in humans, and recently it has become increasingly resistant to the current antifungal agents. In this study we investigated C. albicans dihydroorotate dehydrogenase (DHODH, EC 1.3.99.11), which catalyzes the fourth step of de novo pyrimidine synthesis, as a new target for controlling infection. We propose that the enzyme is a member of the DHODH family 2, which comprises mitochondrially bound enzymes, with quinone as the direct electron acceptor and oxygen as the final electron acceptor. Full-length DHODH and N-terminally truncated DHODH, which lacks the targeting sequence and the transmembrane domain, were subcloned from C. albicans, recombinantly expressed in Escherichia coli, purified, and characterized for their kinetics and substrate specificity. An inhibitor screening with 28 selected compounds was performed. Only the dianisidine derivative, redoxal, and the biphenyl quinoline-carboxylic acid derivative, brequinar sodium, which are known to be potent inhibitors of mammalian DHODH, markedly reduced C. albicans DHODH activity. This study provides a background for the development of antipyrimidines with high efficacy for decreasing in situ pyrimidine nucleotide pools in C. albicans.

Amino Acid Motifs↗
PubMed1993

Brequinar sodium, mycophenolic acid, and cyclosporin A inhibit different stages of IL-4- or IL-13-induced human IgG4 and IgE production in vitro.

We investigated the effect of cyclosporin A (CsA), mycophenolic acid (MPA), and brequinar sodium (BQ) on human IgG4 and IgE synthesis induced by IL-4 or IL-13. BQ inhibited IL-4 and IL-13-induced IgG4 and IgE synthesis in cultures of peripheral blood mononuclear cells (PBMC) or highly purified B cells costimulated by anti-CD40 mAbs in a dose-dependent fashion. CsA and MPA had either suppressive or enhancing effects depending on the concentrations tested. Interestingly, BQ inhibited IgG4 and IgE synthesis at concentrations of 10(-6)-10(-8) M, which did not affect T or B cell proliferation, indicating that the inhibitory effects of BQ on Ig production were not directly related to inhibition of T or B cell proliferation. In contrast, the inhibitory effects of MPA on Ig production were directly associated with inhibitory effects on T and B cell proliferation. CsA blocked T and B cell proliferation at the same concentration (10(-7) M) which enhanced IgG4 and IgE synthesis, indicating that reduction in T or B cell proliferation correlated with enhanced IgE production. CsA also inhibited CD40 ligand expression and IL-2, IL-4, IL-5, IFN-gamma, and GM-CSF production by activated CD4+ T cell clones, whereas MPA and BQ were ineffective, indicating that these compounds do not inhibit early events in T cell activation. Collectively, our data indicate that BQ, MPA, and CsA block different stages of the IgG4 and IgE production process. In addition, we observed that CsA and MPA, in contrast to BQ, at lower concentrations can also have potentiating effects on the production of these Ig isotypes.

Antigens, CD↗