EXPLORING NEW USES OF EXISTING DRUGS AGAINST LIVER STAGE MALARIA

Malaria;Liver stage;Drug discovery;Immunology

Liu, YiSullivan, David J. ;

Johns Hopkins University

关键词: Malaria;    Liver stage;    Drug discovery;    Immunology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37225/LIU-THESIS-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Malaria, as one of the most lethal infectious diseases, has been causing much morbidity and mortality worldwide for decades. The causative parasites, Plasmodium spp., are extremely hard to eliminate because of their intricate life cycle and fast-emerging drug resistance. At present most malaria drug development programs have focused on the blood stages for curative treatment of malaria disease. The liver stage of malaria, an obligatory step of disease progression prior to blood stages, is an area of drug development that has been omitted for a long time because it is cumbersome to grow hepatocytes and parasites for drug screening assays. Liver stage drugs are important for the prophylaxis of all malarias as well as replacing toxic primaquine for dormant stages of P. vivax and P. ovale malaria. Because of the scarcity and urgent need of drugs specific for liver stage malaria, the purpose of this study is to identify novel, potent and non-toxic therapeutic agents from existing drugs and compounds. In collaboration with Gradient Biomodeling we used a virtual screen with a quantum physics model to identify potential novel target molecules. Data from a handful of liver stage in vitro screens including the Novartis dataset of 5,000 molecules was input to create a pharmacophore model and generate similarities utilizing additional quantum physics properties. We screened in silico by quantum modeling many millions of molecules to identify 45 unique potential compounds based on quantum scores. We obtained or synthesized nearly a dozen of those with half showing activity both in single oral dose in mice and in an in vitro liver stage P. berghei model. Prominent amongst the list was an isomer of cethromycin, which is a 3 quinoline with a ketolide. This was active with more than a log decrease in mice and acted synergistically with primaquine. Another simple concept used was identification of drugs with enterohepatic circulation that reach high hepatocyte concentrations relative to plasma like azithromycin, posaconazole, moxifloxacin and even cethromycin. The macrolide hybrids to quinoline may be a potent nontoxic set of molecules for liver stage malaria.