The Development Process for Discovery and Clinical Advancement of Modern Antimalarials

Ashton, Trent D.; Devine, Shane M.; Möhrle, Jörg J.; Laleu, Benoît; Burrows, Jeremy N.; Charman, Susan A.; Creek, Darren J.; Sleebs, Brad E.

doi:10.1021/acs.jmedchem.9b00761

Cited by 62 publications

(51 citation statements)

References 123 publications

(463 reference statements)

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“…In this study, we could not conclusively address whether metabolism was occurring, but this will be an important facet to address in a future mechanistic study of these azalide analogues. The possibility of the macrolactone acting as a delivery vehicle with subsequent metabolic release of the active payload in the parasite raises the prospect for the azithromycin scaffold to be tethered to and act as a delivery vehicle for other antimalarials that act at a similar asexual killing rate to chloroquine, akin to antimalarial candidates undergoing clinical trials such as KAF156 or MMV048 [64]. Such a strategy to improve dual target efficacy of azithromycin analogues, and delay the onset of resistance, is an attractive option.…”

Section: Discussionmentioning

confidence: 99%

Retargeting azithromycin analogues to have dual-modality antimalarial activity

et al. 2020

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Background Resistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed. Azithromycin is a clinically used macrolide antibiotic proposed as a partner drug for combination therapy in malaria, which has also been tested as monotherapy. However, its slow-killing ‘delayed-death’ activity against the parasite’s apicoplast organelle and suboptimal activity as monotherapy limit its application as a potential malaria treatment. Here, we explore a panel of azithromycin analogues and demonstrate that chemical modifications can be used to greatly improve the speed and potency of antimalarial action. Results Investigation of 84 azithromycin analogues revealed nanomolar quick-killing potency directed against the very earliest stage of parasite development within red blood cells. Indeed, the best analogue exhibited 1600-fold higher potency than azithromycin with less than 48 hrs treatment in vitro. Analogues were effective against zoonotic Plasmodium knowlesi malaria parasites and against both multi-drug and artemisinin-resistant Plasmodium falciparum lines. Metabolomic profiles of azithromycin analogue-treated parasites suggested activity in the parasite food vacuole and mitochondria were disrupted. Moreover, unlike the food vacuole-targeting drug chloroquine, azithromycin and analogues were active across blood-stage development, including merozoite invasion, suggesting that these macrolides have a multi-factorial mechanism of quick-killing activity. The positioning of functional groups added to azithromycin and its quick-killing analogues altered their activity against bacterial-like ribosomes but had minimal change on ‘quick-killing’ activity. Apicoplast minus parasites remained susceptible to both azithromycin and its analogues, further demonstrating that quick-killing is independent of apicoplast-targeting, delayed-death activity. Conclusion We show that azithromycin and analogues can rapidly kill malaria parasite asexual blood stages via a fast action mechanism. Development of azithromycin and analogues as antimalarials offers the possibility of targeting parasites through both a quick-killing and delayed-death mechanism of action in a single, multifactorial chemotype.

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Section: Discussionmentioning

confidence: 99%

Retargeting azithromycin analogues to have dual-modality antimalarial activity

et al. 2020

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“…The development pathway for anticryptosporidial drugs is especially challenging, given the lack of a simple in vitro culture system and the need to demonstrate safety and efficacy in young children. Nonetheless, based on recent successes in high-throughput phenotypic screening to identify Cryptosporidium growth inhibitors [ 11 ] and in developing antimalarials targeted for use by pregnant women and children [ 12 ], similar approaches have an excellent chance of identifying safe and effective treatments for Cryptosporidium . Indeed, as summarized in Table 1 , multiple high-quality leads have recently been identified, making adequate pharmaceutical company interest one of the most important remaining impediments.…”

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confidence: 99%

Cryptosporidiosis should be designated as a tropical disease by the US Food and Drug Administration

Choy

Huston

2020

PLoS Negl Trop Dis

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Although the protozoan parasite Cryptosporidium spp. was recognized as a human pathogen in 1976 [1], it was only after a major outbreak in 1993 that sickened more than 400,000 and killed 69 in Milwaukee, Wisconsin, United States of America [2], that its impact as a diarrheal disease-causing pathogen began to be widely appreciated. Cryptosporidium has since been recognized as the most frequently identified pathogen in US waterborne outbreaks [3]. However, because otherwise healthy people recover spontaneously, it continues to be viewed in the US primarily as an opportunistic pathogen causing chronic diarrhea in AIDS patients and other immunocompromised people. In 2013, publication of the first results from the Global Enteric Multicenter Study (GEMS) highlighted the impact of this parasite among children in lowresource settings (LRS), including seven African and Asian countries. Cryptosporidium was found to be one of the three most important diarrhea-causing pathogens in children under 12 months old and the most common cause of mortality due to moderate-to-severe diarrhea among 12-to 23-month olds [4,5]. Subsequent epidemiological studies reinforced these findings, including MAL-ED (Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development) and more recent surveys by the Global Burden of Disease (GBD) and the GEMS-1A follow-on study to GEMS. At eight Asian and African sites, the MAL-ED study found Cryptosporidium was among the five most important pathogens causing diarrhea in community clinics [6]. The GBD study estimated that globally Cryptosporidium is responsible for more than 44.8 million episodes of diarrhea and 48,000 deaths annually [7]. GEMS-1A confirmed and extended the findings from GEMS by showing that Cryptosporidium was associated with a greater than 2-fold increased risk of death among 12-to 23-month olds with moderate-to-severe diarrhea [8]. Despite this substantial and well-documented burden, the impact of cryptosporidiosis is still under-recognized by the wider global health community: Cryptosporidiosis is not designated as a neglected tropical disease (NTD) by the World Health Organization nor is it included on the list of tropical diseases eligible for a priority review voucher (PRV) from the US Food and Drug Administration (FDA). We highlight below the reasons why cryptosporidiosis strongly deserves inclusion on the FDA list of tropical diseases and how this could help stimulate development of improved therapies. The current toolbox of interventions against cryptosporidiosis is severely limited. There are no approved vaccines, and there is only a single anticryptosporidial drug, nitazoxanide. Although nitazoxanide reduces the duration of illness in immunocompetent adults, it is inadequate for the populations with the greatest need. Nitazoxanide is no better than placebo in severely immunocompromised subjects, such as HIV patients [9], and only modestly effective

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“…Some of the earliest synthetic antimalarials targeted DHFR [11][12][13][14][15]. Cycloguanil (1) and pyrimethamine (Pyr) (2), date back to the 1940s [16,17] but long-term widespread use of these molecules has led to resistance through the evolution of multiple mutations in PfDHFR [18][19][20]. The problematic PfDHFR 'quadruple mutant' (QM) has four substitutions of Asn51-Ile and Cys59-Arg as well as active site residues Ser108-Asn and Ile164-Leu ( Figure 1C).…”

Section: Dihydrofolate Reductase -A Resistant Enzyme Made Sensitivementioning

confidence: 99%

Driving antimalarial design through understanding of target mechanism

Calic

Mansouri

Scammells

et al. 2020

Biochemical Society Transactions

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Malaria continues to be a global health threat, affecting approximately 219 million people in 2018 alone. The recurrent development of resistance to existing antimalarials means that the design of new drug candidates must be carefully considered. Understanding of drug target mechanism can dramatically accelerate early-stage target-based development of novel antimalarials and allows for structural modifications even during late-stage preclinical development. Here, we have provided an overview of three promising antimalarial molecular targets, PfDHFR, PfDHODH and PfA-M1, and their associated inhibitors which demonstrate how mechanism can inform drug design and be effectively utilised to generate compounds with potent inhibitory activity.

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The Development Process for Discovery and Clinical Advancement of Modern Antimalarials

Cited by 62 publications

References 123 publications

Retargeting azithromycin analogues to have dual-modality antimalarial activity

Retargeting azithromycin analogues to have dual-modality antimalarial activity

Cryptosporidiosis should be designated as a tropical disease by the US Food and Drug Administration

Driving antimalarial design through understanding of target mechanism

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