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Amodiaquine
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Inhibition of plasmepsin, a protease involved in the digestion of heme within the digestive vacuole, has been shown to be inhibitory to the action of chloroquine, suggesting that unless the FPIX is formed by the oxidation of heme, the chloroquine will not be able to act by inhibiting FPIX breakdown (Moon et al., 1997). This has been repeated in studies of many quinoline antimalarials, including amodiaquine (Mungthin et al., 1998).
New peptide derived antimalaria and antimicrobial agents bearing sulphonamide moiety
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
D. I. Ugwuja, U. C. Okoro, S. S. Soman, R. Soni, S. N. Okafor, D. I. Ugwu
To gain further insight in the binding interactions of our compounds and the drug receptors, we carried out molecular docking studies. Table 2 shows the free binding energy, ΔG (kcal/mol) of the compounds against each selected drug receptor. These ΔG were compared to both the co-crystallized inhibitor and the standard drug. All the compounds studied had a good binding affinity with all the four drug receptors used in this study. Compound 7g had a better binding affinity (−12.91 kcal/mol) with plasmepsin I receptor from P. falciparum (3QS1) when compared to the standard drug, chloroquine (−11.67 kcal/mol). Its binding affinity was not significantly different from the co-crystallized inhibitor. Similarly compounds 7a and 7h had a better binding affinity with plasmepsin II receptor from P. falciparum (1SME) when compared to both the co-crystallized inhibitor and the standard drug. Compounds 7b and 7n showed good binding affinities with penicillin-binding protein 1B (2Y2G) and E. coli DNA gyrase (5MMN).
Developments in drug design strategies for bromodomain protein inhibitors to target Plasmodium falciparum parasites
Published in Expert Opinion on Drug Discovery, 2020
Hanh H. T. Nguyen, Lee M. Yeoh, Scott A. Chisholm, Michael F. Duffy
Another genetic approach to identifying specific inhibitors for PfBDPs is to utilize transgenic parasites expressing altered levels of the target PfBDP. This concept was pioneered in yeast [98] but can be applied to any pathogen. For example, P. falciparum parasites underexpressing and overexpressing the ER-resident aspartyl protease plasmepsin V were tested for altered sensitivity to putative inhibitors of plasmepsin V [99]. Josling et al. (2015) generated transgenic parasite lines with conditional knockdown or overexpression of PfBDP1 [53], these could be used as tools to indicate the specificity of hit compounds for PfBDP1.
Signal peptide peptidase: a potential therapeutic target for parasitic and viral infections
Published in Expert Opinion on Therapeutic Targets, 2022
Christopher Schwake, Michael Hyon, Athar H. Chishti
The essentiality of SPP in other Apicomplexa infections is now beginning to emerge. Babesiosis is an emerging zoonotic infection spread through the bite of Ioxedes scapularis ticks. The prevalence of babesiosis is increasing in New England and the Western regions of the United States due to infection primarily with B. microti. Risk factors for severe babesiosis include advanced age, HIV status, and immunomodulating drugs/procedures. The mortality rate of infection ranges from 6–21% and up to 57% of immunocompromised patients can develop end-organ complications [40,41]. Babesiosis also affects livestock husbandry as widespread infection can cause substantial economic loss to farmers [42]. Babesiosis is becoming difficult to manage as there is evidence of resistance emerging to azithromycin and atovaquone [43]. Therefore, to combat emerging drug resistant Babesia parasites, new molecular targets need to be identified. Our laboratory demonstrated for the first time that Babesia microti SPP is a viable drug target due to inhibition using the SPP inhibitor (Z-LL)2 ketone on intraerythrocytic growth [28]. Furthermore, FDA-approved HIV protease inhibitors lopinavir and atazanavir were able to kill B. microti in an extraerythrocytic assay as well as in a mouse challenge [28]. Atazanavir appeared to exhibit targeted selectivity toward parasite SPP over mammalian SPP, but more direct studies are needed to confirm this inhibitor selectivity. Additionally, the exact mechanism of how lopinavir and other HIV protease inhibitors act on human parasitic infections has not been definitively demonstrated. The plasmepsin aspartyl protease family responsible for hemoglobin degradation in malaria food vacuoles is another potential target. Due to HIV protease inhibitors exhibiting liver stage and transmission blocking activity, targets beyond plasmepsin are also feasible. As Babesia and other parasites do not form food vacuoles during their life cycle, it is possible that a highly conserved cellular target is responsible for the therapeutic effect of these inhibitors. Parasite SPP is a potential candidate for this target due to its essential role in maintaining ER homeostasis.