Kinases GO analysis.

Eumycetoma is a neglected tropical subcutaneous disease most commonly caused by the fungus Madurella mycetomatis. Currently, eumycetoma is treated by a combination of antifungal therapy and surgery, with limited success rates. To identify novel drug targets we used an in silico approach to determine the kinases present in M. mycetomatis genome and rank them as potential drug targets. In total 132 predicted kinases were identified in M. mycetomatis, of which 21 were predicted to be essential for fungal viability and 4 of these had no human orthologues. Two were linked to the Cell Wall Integrity (CWI) signalling pathway and were expressed in a Galleria mellonella infection model. Several kinase inhibitors were identified after in silico modelling, however only 8 were able to inhibit growth. Five had predicted binding affinity with components of the CWI. Altogether, the CWI shows potential as a drug target for further evaluation.

真菌性足菌肿（Eumycetoma）是一种被忽视的热带皮下疾病，其最常见的致病真菌为马杜拉霉（Madurella mycetomatis）。目前，该病的临床治疗采用抗真菌治疗与外科手术联合方案，但疗效有限。为鉴定新型药物靶点，本研究采用计算机模拟（in silico）方法，对马杜拉霉基因组中的激酶进行预测，并将其作为潜在药物靶点进行优先级排序。研究团队总计在马杜拉霉中鉴定出132个预测激酶，其中21个被预测为真菌存活所必需，且这21个激酶中有4个不存在人类同源基因。在上述4个激酶中，有2个与细胞壁完整性（Cell Wall Integrity, CWI）信号通路相关，并在大蜡螟（Galleria mellonella）感染模型中呈现表达。通过计算机模拟建模，研究人员筛选出多种激酶抑制剂，但仅8种可抑制真菌生长，其中5种与CWI通路组分具有预测结合亲和力。综上，CWI通路具备作为进一步评估的药物靶点的潜力。