作者: Vydyam, Pratap ; Cornillot, Emmanuel ; Zhao, Wenyi ; Terpinski, Jacek ; Chand, Meenal ; Jacobus, Laura R. ; Renard, Isaline ; Shah, Raju ; Shieh, Hong-Ming ; Saionz, Kurt W. ; Jacobus, David P. ; Gihaz, Shalev ; Heffernan, Gavin D. ; Ben Mamoun, Choukri

ABSTRACTBabesia and Plasmodium pathogens, the causative agents of babesiosis and malaria, are vector-borne intraerythrocytic protozoan parasites, posing significant threats to both human and animal health. The widespread resistance exhibited by these pathogens to various classes of antiparasitic drugs underscores the need for the development of novel and more effective therapeutic strategies. Antifolates have long been recognized as attractive antiparasitic drugs as they target the folate pathway, which is essential for the biosynthesis of purines and pyrimidines, and thus is vital for the survival and proliferation of protozoan parasites. More efficacious and safer analogs within this class are needed to overcome challenges due to resistance to commonly used antifolates, such as pyrimethamine, and to address liabilities associated with the dihydrotriazines, WR99210 and JPC-2067. Here, we utilized an in vitro culture condition suitable for the continuous propagation of Babesia duncani, Babesia divergens, Babesia MO1, and Plasmodium falciparum in human erythrocytes to screen a library of 50 dihydrotriazines and 29 biguanides for their efficacy in vitro and compared their potency and therapeutic indices across different species and isolates. We identified nine analogs that inhibit the growth of all species, including the P. falciparum pyrimethamine-resistant strain HB3, with IC 50 values below 10 nM, and display excellent in vitro therapeutic indices. These compounds hold substantial promise as lead antifolates for further development as broad-spectrum antiparasitic drugs.

2023-12-01·Chemical Biology & Drug Design

Hybrid PABA‐glutamic acid conjugated 1,3,5‐triazine derivatives: Design, synthesis, and antimalarial activity screening targeting Plasmodium falciparum dihydro folate reductase enzyme

Article

作者: Patgiri, Saurav Jyoti ; Adhikari, Nayana ; Bhat, Hans Raj ; Ghosh, Surajit Kumar ; Saha, Ashmita ; Vinayagam, Sathishkumar ; Choudhury, Ayesha Aktar Khanam

AbstractDespite the successful reduction in the malaria health burden in recent years, it continues to remain a significant global health problem mainly because of the emerging resistance to first‐line treatments. Also because of the disruption in malaria prevention services during the COVID‐19 pandemic, there was an increase in malaria cases in 2021 compared to 2020. Hence, the present study outlined the in silico study, synthesis, and antimalarial evaluation of 1,3,5‐triazine hybrids conjugated with PABA‐glutamic acid. Docking study revealed higher binding energy compared to the originally bound ligand WR99210, predominant hydrogen bond interaction, and involvement of key amino acid residues, like Arg122, Ser120, and Arg59. Fourteen compounds were synthesized using traditional and microwave synthesis. The in vitro antimalarial evaluation against chloroquine‐sensitive 3D7 and resistant Dd2 strain of Plasmodium falciparum showed a high to moderate activity range. Compounds C1 and B4 showed high efficacy against both strains and a further study revealed that compound C1 is non‐cytotoxic against the HEK293 cell line with no acute oral toxicity. In vivo, study was performed for the most potent antimalarial compound C1 to optimize the research work and found to be effectively suppressing parasitemia of Plasmodium berghei strain in the Swiss albino mice model.

2023-05-01·Nature microbiology

Babesia duncani multi-omics identifies virulence factors and drug targets.

Article

作者: Hu, Yangyang ; Chakravarty, Sakshar ; Liang, Qihua ; Montero, Estrella ; Harb, Omar S. ; Fang, Tiffany ; Ma, Wenxiu ; Munshi, Muhammad ; Sanchez, Sergio ; Vydyam, Pratap ; Lonardi, Stefano ; Gonzalez, Luis Miguel ; Cornillot, Emmanuel ; Le Roch, Karine G. ; Estrada, Karel ; Sanchez-Flores, Alejandro ; Lu, Xueqing Maggie ; Singh, Pallavi ; Ciampossin, Loic ; Gihaz, Shalev ; Gupta, Mohit ; Abel, Steven ; Khabirova, Eleonora ; Batugedara, Gayani ; Thekkiniath, Jose ; Mamoun, Choukri Ben ; Lenz, Todd

Babesiosis is a malaria-like disease in humans and animals that is caused by Babesia species, which are tick-transmitted apicomplexan pathogens. Babesia duncani causes severe to lethal infection in humans, but despite the risk that this parasite poses as an emerging pathogen, little is known about its biology, metabolic requirements or pathogenesis. Unlike other apicomplexan parasites that infect red blood cells, B. duncani can be continuously cultured in vitro in human erythrocytes and can infect mice resulting in fulminant babesiosis and death. We report comprehensive, detailed molecular, genomic, transcriptomic and epigenetic analyses to gain insights into the biology of B. duncani. We completed the assembly, 3D structure and annotation of its nuclear genome, and analysed its transcriptomic and epigenetics profiles during its asexual life cycle stages in human erythrocytes. We used RNA-seq data to produce an atlas of parasite metabolism during its intraerythrocytic life cycle. Characterization of the B. duncani genome, epigenome and transcriptome identified classes of candidate virulence factors, antigens for diagnosis of active infection and several attractive drug targets. Furthermore, metabolic reconstitutions from genome annotation and in vitro efficacy studies identified antifolates, pyrimethamine and WR-99210 as potent inhibitors of B. duncani to establish a pipeline of small molecules that could be developed as effective therapies for the treatment of human babesiosis.

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适应症	最高研发状态	国家/地区	公司	日期
疟疾	临床前	-	Jacobus Pharmaceutical Co., Inc.	-
细胞内鸟分枝杆菌感染	临床前	-	Jacobus Pharmaceutical Co., Inc.	-
肺孢子菌肺炎	临床前	-	Jacobus Pharmaceutical Co., Inc.	-