Ramakrishnan Gayatri, Chandra Nagasuma, Srinivasan Narayanaswamy
Indian Institute of Science Mathematics Initiative, Indian Institute of Science, Bangalore, 560012, India.
Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560012, India.
Malar J. 2017 Jul 18;16(1):290. doi: 10.1186/s12936-017-1937-2.
The critically important issue on emergence of drug-resistant malarial parasites is compounded by cross resistance, where resistance to one drug confers resistance to other chemically similar drugs or those that share mode of action. This aspect requires discovery of new anti-malarial compounds or formulation of new combination therapy. The current study attempts to contribute towards accelerating anti-malarial drug development efforts, by exploring the potential of existing FDA-approved drugs to target proteins of Plasmodium falciparum.
Using comparative sequence and structure analyses, FDA-approved drugs, originally developed against other pathogens, were identified as potential repurpose-able candidates against P. falciparum. The rationale behind the undertaken approach is the likeliness of small molecules to bind to homologous targets. Such a study of evolutionary relationships between established targets and P. falciparum proteins aided in identification of approved drug candidates that can be explored for their anti-malarial potential.
Seventy-one FDA-approved drugs were identified that could be repurposed against P. falciparum. A total of 89 potential targets were recognized, of which about 70 are known to participate in parasite housekeeping machinery, protein biosynthesis, metabolic pathways and cell growth and differentiation, which can be prioritized for chemotherapeutic interventions. An additional aspect of prioritization of predicted repurpose-able drugs has been explored on the basis of ability of the drugs to permeate cell membranes, i.e., lipophilicity, since the parasite resides within a parasitophorous vacuole, within the erythrocyte, during the blood stages of infection. Based on this consideration, 46 of 71 FDA-approved drugs have been identified as feasible repurpose-able candidates against P. falciparum, and form a first-line for laboratory investigations. At least five of the drugs identified in the current analysis correspond to existing antibacterial agents already under use as repurposed anti-malarial agents.
The drug-target associations predicted, primarily by taking advantage of evolutionary information, provide a valuable resource of attractive and feasible candidate drugs that can be readily taken through further stages of anti-malarial drug development pipeline.
耐药疟原虫的出现这一极其重要的问题因交叉耐药而更加复杂，即对一种药物的耐药性会导致对其他化学结构相似或作用方式相同的药物产生耐药性。这方面需要发现新的抗疟化合物或制定新的联合疗法。当前的研究试图通过探索现有FDA批准药物靶向恶性疟原虫蛋白质的潜力，为加速抗疟药物研发工作做出贡献。
通过比较序列和结构分析，将最初针对其他病原体开发的FDA批准药物鉴定为针对恶性疟原虫的潜在可重新利用的候选药物。所采用方法背后的基本原理是小分子与同源靶点结合的可能性。对既定靶点与恶性疟原虫蛋白质之间进化关系的此类研究有助于鉴定可探索其抗疟潜力的批准药物候选物。
鉴定出71种可重新用于治疗恶性疟原虫的FDA批准药物。总共识别出89个潜在靶点，其中约70个已知参与寄生虫的基础维持机制、蛋白质生物合成、代谢途径以及细胞生长和分化，这些可作为化疗干预的优先靶点。基于药物渗透细胞膜的能力，即亲脂性，对预测的可重新利用药物的优先排序的另一个方面进行了探索，因为在感染的血液阶段，寄生虫存在于红细胞内的寄生泡中。基于这一考虑，71种FDA批准药物中的46种已被鉴定为针对恶性疟原虫的可行的可重新利用候选药物，并构成实验室研究的第一线。当前分析中鉴定出的至少五种药物对应于已作为重新利用的抗疟药物使用的现有抗菌剂。
主要通过利用进化信息预测的药物-靶点关联提供了有吸引力且可行的候选药物的宝贵资源，这些药物可轻松进入抗疟药物研发管道的进一步阶段。
