Targeting the Liver Stage of Malaria Parasites: A Yet Unmet Goal

Rodrigues, Tiago; Prudêncio, Miguel; Moreira, Rui; Mota, Maria M.; Lopes, Francisca

doi:10.1021/jm201095h

Cited by 74 publications

(74 citation statements)

References 145 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The dearth of antimalarial drugs with antihypnozoite activity remains a major hurdle to overcome in the fight for malaria eradication. Nonetheless, targeting the Plasmodium liver stage offers several opportunities when it comes to developing new prophylactic and curative drugs, as well as vaccines against malaria, because of the lower number of parasites present in the liver as compared with the blood stage (6,63). However, this stage remains largely unexplored because of the scarcity of research models to investigate the underlying mechanisms of infection of human hepatocytes by Plasmodium species.…”

Section: Challenges and Current State Of Malaria Drug Developmentmentioning

confidence: 99%

“…In the case of P. vivax and P. ovale infections, relapse is often seen as a result of hypnozoites, dormant forms of the parasites in hepatic cells that can reactivate weeks or months after the primary infection (4). Targeting the development of liver-stage Plasmodium parasites represents a promising strategy for the development of malaria prophylaxis and presents a route to address disease eradication (5)(6)(7). Malaria eradication requires transmission-blocking strategies, and by intervening during the liver stage the development of both merozoites and gametocytes is prevented.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Current therapies and future possibilities for drug development against liver-stage malaria

Raphemot¹,

Posfai²,

Derbyshire³

2016

Journal of Clinical Investigation

View full text Add to dashboard Cite

Section: Challenges and Current State Of Malaria Drug Developmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Current therapies and future possibilities for drug development against liver-stage malaria

Raphemot¹,

Posfai²,

Derbyshire³

2016

Journal of Clinical Investigation

View full text Add to dashboard Cite

“…Malaria pathology is caused by the blood stages of singlecelled parasites of the genus Plasmodium. However, before the symptomatic infection of red blood cells, Plasmodium parasites undergo an obligatory and clinically silent developmental phase in the liver, which constitutes an ideal target for disease prevention (1,2). The liver stage of Plasmodium infection occurs after sporozoites are injected into the skin of the mammalian host upon a blood meal of an infected female Anopheles mosquito (3).…”

mentioning

confidence: 99%

Plasmodium berghei EXP-1 interacts with host Apolipoprotein H during Plasmodium liver-stage development

Cunha

Nyboer

Heiß

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The first, obligatory replication phase of malaria parasite infections is characterized by rapid expansion and differentiation of single parasites in liver cells, resulting in the formation and release of thousands of invasive merozoites into the bloodstream. Hepatic Plasmodium development occurs inside a specialized membranous compartment termed the parasitophorous vacuole (PV). Here, we show that, during the parasite's hepatic replication, the C-terminal region of the parasitic PV membrane protein exported protein 1 (EXP-1) binds to host Apolipoprotein H (ApoH) and that this molecular interaction plays a pivotal role for successful Plasmodium liver-stage development. Expression of a truncated EXP-1 protein, missing the specific ApoH interaction site, or down-regulation of ApoH expression in either hepatic cells or mouse livers by RNA interference resulted in impaired intrahepatic development. Furthermore, infection of mice with sporozoites expressing a truncated version of EXP-1 resulted in both a significant reduction of liver burden and delayed blood-stage patency, leading to a disease outcome different from that generally induced by infection with wildtype parasites. This study identifies a host-parasite protein interaction during the hepatic stage of infection by Plasmodium parasites. The identification of such vital interactions may hold potential toward the development of novel malaria prevention strategies. malaria | Plasmodium liver stages | host-parasite interaction | ApoH | EXP-1

show abstract

“…At present, drugs acting against parasite liver forms are scarce, and primaquine (PQ, 1 in Scheme 1) remains the only drug in clinical use that acts against liver stages of all Plasmodium species, 4 including P. vivax and P. ovale hypnozoites.…”

mentioning

confidence: 99%

PRIMACINS, N-cinnamoyl-primaquine conjugates, with improved liver-stage antimalarial activity

Pérez¹,

Teixeira²,

Albuquerque³

et al. 2012

Med. Chem. Commun.

Self Cite

View full text Add to dashboard Cite

Novel primaquine derivatives, obtained by conjugation of the drug's aliphatic amine with different cinnamic acids, resulted in increased in vitro activity, compared to primaquine, against liver-stage malarial parasites. The compounds were non-cytotoxic to human hepatoma cells, suggesting that they are a promising new class of agents for the treatment and prevention of malaria.Effective and safe antimalarial drugs active against both liver and erythrocytic parasite stages will be valuable components of malaria eradication strategies.1 Mammalian infection by malarial parasites is initiated by an infected mosquito bite, followed by a clinically silent liver-stage infection, during which thousands of merozoites are formed to be released into the bloodstream and trigger the clinically relevant erythrocytic stage of the life cycle. 2Drugs able to act on the liver stage are highly relevant, as they can be used in chemoprophylaxis to prevent all clinical manifestations of malaria.3 Moreover, such drugs are particularly relevant in P. vivax and P. ovale infections, as in these species latent forms that are called hypnozoites are not eliminated by most available therapies, persist in the liver for long periods, and subsequently cause malaria relapses. At present, drugs acting against parasite liver forms are scarce, and primaquine (PQ, 1 in Scheme 1) remains the only drug in clinical use that acts against liver stages of all Plasmodium species, 4 including P. vivax and P. ovale hypnozoites.5 Unfortunately, PQ's low oral bioavailability and high hemotoxicity hold back its clinical use, especially in vulnerable populations including pregnant women, infants and the elderly. In addition, PQ causes hemolysis in patients with congenital deficiency of glucose-6-phosphate dehydrogenase, 5 complicating its use to treat P. vivax and P. ovale malaria and limiting its use in chemoprophylaxis.For the past decade, we have been working on chemical approaches to mask the PQ aliphatic amine in order to obtain analogues resistant to oxidative deamination, the major metabolic pathway underlying the drug's low oral bioavailability (Scheme 1) by conversion into an inactive metabolite, carboxyprimaquine (2 in Scheme 1).5 To this end, we have successfully developed imidazoquines (3 in Scheme 1) 6,7 and primacenes (4 in Scheme 1), 8,9 peptidomimetic and organometallic derivatives of PQ with promising antimalarial properties, respectively. Now, we disclose a new family of PQ derivatives, the PRIMACINS (5 in Scheme 1), obtained by coupling PQ to cinnamic acids, as the latter was formerly reported to possess interesting antimalarial properties.10 PRIMACINS were found to have higher in vitro activity than PQ against the liver-stage of the rodent malarial parasite P. berghei (Fig. 1).PRIMACINS were tested against liver stages of the rodent parasite P. berghei and against erythrocytic stages of the human parasite P. falciparum (Table 1). Compounds 5 were two-or more-fold more potent than PQ against liver stage P. berghei and were non-toxic to Huh7 hum...

show abstract

Targeting the Liver Stage of Malaria Parasites: A Yet Unmet Goal

Cited by 74 publications

References 145 publications

Current therapies and future possibilities for drug development against liver-stage malaria

Current therapies and future possibilities for drug development against liver-stage malaria

Plasmodium berghei EXP-1 interacts with host Apolipoprotein H during Plasmodium liver-stage development

PRIMACINS, N-cinnamoyl-primaquine conjugates, with improved liver-stage antimalarial activity

Contact Info

Product

Resources

About