Das Mousumi, Singh Shalini, Dubey Vikash Kumar
Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam, 781039, India.
Chem Biol Drug Des. 2016 Mar;87(3):352-60. doi: 10.1111/cbdd.12665. Epub 2015 Oct 13.
Ornithine decarboxylase (LdODC), a key enzyme in polyamine biosynthesis in Leishmania donovani, catalyzes the conversion of ornithine to putrescine that is finally used for synthesis of spermidine and other polyamines. Inhibition of ornithine decarboxylase is likely to deplete the parasite trypanothione and may result in increased reactive oxygen species (ROS). Sequence as well as structure of LdODC and human ODC shows significant difference; therefore, we have identified novel specific inhibitors of LdODC. These inhibitors are able to inhibit recombinant LdODC and decrease intracellular putrescine concentration showing target specificity. The Ki values of LdODC inhibition do not correlate with IC50 values in Leishmania promastigote possibly due to different stability/pharmacokinetics. These inhibitors, except compound M-5, have only minor effect on Leishmania promastigotes, and IC50 values are several folds higher as compared to Ki values. In case of compound M-5, IC50 value is less than Ki value indicating that the compound may have additional targets. Our studies suggest that the parasite resists these LdODC inhibitors by overexpression of spermidine synthase mRNA.
鸟氨酸脱羧酶（LdODC）是杜氏利什曼原虫多胺生物合成中的关键酶，催化鸟氨酸转化为腐胺，腐胺最终用于亚精胺和其他多胺的合成。抑制鸟氨酸脱羧酶可能会耗尽寄生虫的锥虫硫醇，并可能导致活性氧（ROS）增加。LdODC和人类ODC的序列以及结构显示出显著差异；因此，我们鉴定出了LdODC的新型特异性抑制剂。这些抑制剂能够抑制重组LdODC并降低细胞内腐胺浓度，显示出靶标特异性。LdODC抑制的Ki值与利什曼原虫前鞭毛体中的IC50值不相关，这可能是由于稳定性/药代动力学不同。这些抑制剂，除了化合物M-5，对利什曼原虫前鞭毛体只有轻微影响，并且IC50值比Ki值高几倍。就化合物M-5而言，IC50值小于Ki值，表明该化合物可能有其他靶标。我们的研究表明，寄生虫通过过表达亚精胺合酶mRNA来抵抗这些LdODC抑制剂。
