Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the opportunistic fungal pathogen Cryptococcus neoformans via cyclophilin-dependent inhibition of calcineurin
Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the opportunistic fungal pathogen Cryptococcus neoformans via cyclophilin-dependent inhibition of calcineurin
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DOI：
10.1128/aac.44.1.143-149.2000
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发表时间：
2000-01-01
影响因子：
4.9
通讯作者：
Heitman, J
中科院分区：
文献类型：
--
作者：
Cruz, MC;Del Poeta, M;Heitman, J
环孢素（CsA）是一种免疫抑制和抗菌药物，与亲环蛋白A配合，抑制蛋白磷酸酶钙调磷酸酶。我们最近发现，新型隐球菌在24℃下生长对CsA有抗性，但在37℃下生长敏感，并且钙调磷酸酶是37℃下生长和致病性所必需的。本研究筛选了CsA类似物对体外新生梭状菌的毒性。在大多数情况下，抗真菌活性与体外亲环蛋白A结合和细胞培养中混合淋巴细胞反应和白细胞介素2产生的抑制有关。鉴定出两种不同寻常的非免疫抑制CsA衍生物（γ - oh） MeLeu(4)-Cs（211-810）和D-Sar (α - sme)(3) Val(2)-DH-Cs(209-825)，它们也对新生c具有毒性。这些CsA类似物通过真菌亲环蛋白A和钙调磷酸酶同源物抑制新生C.。我们的研究结果确定钙调磷酸酶是一种新的抗真菌药物靶点，并表明非免疫抑制的CsA类似物值得研究作为抗真菌药物。
Cyclosporine (CsA) is an immunosuppressive and antimicrobial drug which, in complex with cyclophilin A, inhibits the protein phosphatase calcineurin. We recently found that Cryptococcus neoformans growth is resistant to CsA at 24 degrees C but sensitive at 37 degrees C and that calcineurin is required for growth at 37 degrees C and pathogenicity. Here CsA analogs were screened far toxicity against C. neoformans in vitro. In most cases, antifungal activity was correlated,vith cyclophilin A binding in vitro and inhibition of the mixed-lymphocyte reaction and interleukin 2 production in cell culture. Two unusual nonimmunosuppressive CsA derivatives, (gamma-OH) MeLeu(4)-Cs (211-810) and D-Sar (alpha-SMe)(3) Val(2)-DH-Cs (209-825), which are also toxic to C. neoformans were identified. These CsA analogs inhibit C. neoformans via fungal cyclophilin A and calcineurin homologs. Our findings identify calcineurin as a novel antifungal drug target and suggest nonimmunosuppressive CsA analogs warrant investigation as antifungal agents.