Repositioning of astemizole for malaria

Malaria remains one of the most important parasitic infectious diseases as far as human suffering is concerned. With almost half of the world's population at risk, its burden is felt worldwide as seen by the high number of deaths recorded each year (405,000 in 2018: WHO World Malaria Report 2019). Unfortunately, over 90% of this mortality rate is recorded in Africa alone, with the highest risk being in children under the age of five (5) and pregnant women. Partly, this is due to the unfortunate spread of resistance to most drugs that were once effective and safe, including Artemisinins which form the basis of the current first-line regimen in the treatment of malaria. For this reason, it is crucial to invest research efforts using various approaches in the drug discovery arsenal to develop novel, and structurally diverse antimalarials with different modes of action. These new antimalarials should not only be able to circumvent resistance but need to be efficacious at different life cycle stages of the parasite (multi-stage activity). This Ph.D. project pursued a drug repositioning approach on Astemizole (AST, Figure 1), a second-generation antihistamine drug which was previously identified as an antimalarial agent by Chong et al., at the Johns Hopkins University School of Medicine through via a high-throughput screening (HTS) of diverse marketed drugs. AST was active against chloroquine-sensitive (CQ-S) and multi-drug resistant (MDR) laboratory strains of the human malaria parasite Plasmodium falciparum (P. falciparum) and demonstrated in vivo efficacy in two mouse infection models of malaria namely, P. Vinckei and P. Yoelii. However, in addition to its low solubility, AST possesses a serious and fatal cardiotoxicity risk, evidenced by its ability to potently inhibit the human ether-á-go-go-related gene (hERG) encoded potassium (K+) channels. This liability led to the withdrawal of AST in most countries during the late 1970's and it is still being discontinued for use in some countries to date

A diverse view of science to catalyse change

Valuing diversity leads to scientific excellence, the progress of science and, most importantly, it is simply the right thing to do. We must value diversity not only in words, but also in actions

A diverse view of science to catalyse change:Valuing diversity leads to scientific excellence, the progress of science and, most importantly, it is simply the right thing to do. we must value diversity not only in words, but also in actions

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Multistage antiplasmodium activity of astemizole analogues and inhibition of hemozoin formation as a contributor to their mode of action

A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against the Plasmodium parasite's life cycle of the subsequent analogues was examined by evaluating against the parasite asexual blood, liver, and sexual gametocytic stages. In addition, the previously reported contribution of heme detoxification to the compound's mode of action was interrogated. Ten of the 17 derivatives showed half-maximal inhibitory concentrations (IC; 50; s) of <0.1 μM against the chloroquine (CQ)-sensitive Plasmodium falciparum NF54 ( PfNF54) strain while maintaining submicromolar potency against the multidrug-resistant strain, PfK1, with most showing low likelihood of cross-resistance with CQ. Selected analogues ( PfNF54-IC; 50; < 0.1 μM) were tested for cytotoxicity on Chinese hamster ovarian (CHO) cells and found to be highly selective (selectivity index > 100). Screening of AST and its analogues against gametocytes revealed their moderate activity (IC; 50; : 1-5 μM) against late stage P. falciparum gametocytes, while the evaluation of activity against P. berghei liver stages identified one compound (3) with 3-fold greater activity than the parent AST compound. Mechanistic studies showed a strong correlation between in vitro inhibition of β-hematin formation by the AST derivatives and their antiplasmodium IC; 50; s. Analyses of intracellular inhibition of hemozoin formation within the parasite further yielded signatures attributable to a possible perturbation of the heme detoxification machinery

A Diverse View of Science to Catalyse Change

Valuing diversity leads to scientific excellence, the progress of science and most importantly, it is simply the right thing to do. We can value diversity not only in words, but also in actions. From the structure of DNA,1 to computer science,2 and space-station batteries,3 several key scientific discoveries that enhance our lives today, were made by marginalized scientists. These three scientists, Rosalind E. Franklin, Alan M. Turing and Olga D. González-Sanabria, did not conform to the cultural expectations of how scientists should look and behave. Unfortunately, marginalized scientists are often viewed as just a resource rather than the lifeblood that constitutes science itself. We need to embrace scientists from all walks of life and corners of the globe; this will also mean that nobody is excluded from tackling the life-threatening societal challenges that lie ahead. An awareness of science policy is essential to safeguarding our future. Science policy deals with creating the framework and codes of conduct that determine how science can best serve society.4-6 Discussions around science policy are often accompanied by anecdotes of “good” and “bad” practices regarding the merits of diversity and inclusion. Excellence and truth, which flow inexorably from diversity and inclusion, are the bedrocks upon which science should influence political and economic outcomes. A vital area of science policy is to support the professional development of marginalized scientists, an objective that must be acted upon by scientific leaders and communicators..