Recently licensed subunit vaccines represent the first and, thus far, the only approved agents for vaccination against malaria. However, these vaccines still fail to confer highly effective ...long-lasting protective immunity. Whole-organism vaccines, employing attenuated
Plasmodium
sporozoites as immunization agents, constitute a promising alternative for highly effective malaria vaccination. In this issue of
EMBO Molecular Medicine
, Goswami et al (
2024
) report on the generation and pre-clinical characterization of genetically attenuated
Plasmodium
parasites, termed LARC2, whose development arrests at late stages of liver infection. Their results warrant the clinical evaluation of PfSPZ-LARC2 towards its use as a whole-organism vaccine against malaria.
D. Moita and M. Prudêncio discuss the study by Goswami et al, in this issue of
EMBO Mol. Med
., on the generation and pre-clinical characterization of late liver stage-arresting genetically attenuated
Plasmodium
parasites as a potential vaccine against malaria.
Ivermectin is a powerful endectocide, which reduces the incidence of vector-borne diseases. Besides its strong insecticidal effect on mosquito vectors of the disease, ivermectin inhibits Plasmodium ...falciparum sporogonic and blood stage development and impairs Plasmodium berghei development inside hepatocytes, both in vitro and in vivo. Herein, we present the first report on structural modification of ivermectin to produce dual-action molecular hybrids with good structure-dependent in vitro activity against both the hepatic and erythrocytic stages of P. berghei and P. falciparum infection, suggesting inclusion of ivermectin antimalarial hybrids in malaria control strategies. The most active hybrid displayed over threefold and 10-fold higher in vitro activity than ivermectin against hepatic and blood stage infections, respectively. Although an overwhelming insecticidal effect against Anopheles stephensi mosquitoes in laboratory conditions was not noticed, in silico docking analysis supports allosteric binding to glutamate-gated chloride channels similar to ivermectin.
Malaria remains one of the most prevalent infectious diseases worldwide, primarily affecting some of the most vulnerable populations around the globe. Despite achievements in the treatment of this ...devastating disease, there is still an urgent need for the discovery of new drugs that tackle infection by
parasites. However, de novo drug development is a costly and time-consuming process. An alternative strategy is to evaluate the anti-plasmodial activity of compounds that are already approved for other purposes, an approach known as drug repurposing. Here, we will review efforts to assess the anti-plasmodial activity of existing drugs, with an emphasis on the obligatory and clinically silent liver stage of infection. We will also review the current knowledge on the classes of compounds that might be therapeutically relevant against
in the context of other communicable diseases that are prevalent in regions where malaria is endemic. Repositioning existing compounds may constitute a faster solution to the current gap of prophylactic and therapeutic drugs that act on
parasites, overall contributing to the global effort of malaria eradication.
In 1967, pioneering work by Ruth Nussenzweig demonstrated for the first time that irradiated sporozoites of the rodent malaria parasite
Plasmodium berghei
protected mice against a challenge with ...infectious parasites of the same species. This remarkable finding opened up entirely new prospects of effective vaccination against malaria using attenuated sporozoites as immunization agents. The potential for whole-sporozoite-based immunization in humans was established in a clinical study in 1973, when a volunteer exposed to X-irradiated
P. falciparum
sporozoites was found to be protected against malaria following challenge with a homologous strain of this parasite. Nearly five decades later, much has been achieved in the field of whole-sporozoite malaria vaccination, and multiple reports on the clinical evaluation of such candidates have emerged. However, this process has known different paces before and after the turn of the century. While only a few clinical studies were published in the 1970’s, 1980’s and 1990’s, remarkable progress was made in the 2000’s and beyond. This article reviews the history of the clinical assessment of whole-sporozoite malaria vaccines over the last forty-nine years, highlighting the impressive achievements made over the last few years, and discussing some of the challenges ahead.
Plasmodium sporozoites are deposited in the skin of their vertebrate hosts through the bite of an infected female Anopheles mosquito. Most of these parasites find a blood vessel and travel in the ...peripheral blood circulation until they reach the liver sinusoids. Once there, the sporozoites cross the sinusoidal wall and migrate through several hepatocytes before they infect a final hepatocyte, with the formation of a parasitophorous vacuole, in which the intrahepatic form of the parasite grows and multiplies. During this period, each sporozoite generates thousands of merozoites. As the development of Plasmodium sporozoites inside hepatocytes is an obligatory step before the onset of disease, understanding the parasite's requirements during this period is crucial for the development of any form of early intervention. This Review summarizes our current knowledge on this stage of the Plasmodium life cycle.
Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. All high-throughput malaria drug discovery efforts have focused on the cyclic ...blood stage, which has limited potential for the prophylaxis, transmission blocking, and eradication efforts that will be needed in the future. To address these unmet needs, a high-throughput phenotypic liver-stage Plasmodium parasite screen was developed to systematically identify molecules with liver-stage efficacy. The screen recapitulates liver-stage infection by isolating luciferase-expressing Plasmodium berghei parasites directly from the salivary glands of infected mosquitoes, adding them to confluent human liver cells in 384-well plates, and measuring luciferase activity after a suitable incubation period. Screening 5,375 known bioactive compounds identified 37 liver-stage malaria inhibitors with diverse modes of action, as shown by inhibition time course experiments. Further analysis of the hits in the Food and Drug Administration-approved drug subset revealed compounds that seem to act specifically on the liver stage of infection, suggesting that this phase of the parasite’s life cycle presents a promising area for new drug discovery. Notably, many active compounds in this screen have molecular structures and putative targets distinctly different from those of known antimalarial agents.
The transmissible forms of Plasmodium parasites result from a process of sporogony that takes place inside their obligatory mosquito vector and culminates in the formation of mammalian-infective ...parasite forms. Ivermectin is a member of the avermectin family of endectocides, which has been proposed to inhibit malaria transmission due its insecticidal effect. However, it remains unclear whether ivermectin also exerts a direct action on the parasite's blood and transmission stages.
We employed a rodent model of infection to assess the impact of ivermectin treatment on P. berghei asexual and sexual blood forms in vivo. We then made use of a newly established luminescence-based methodology to evaluate the activity of ivermectin and other avermectins against the sporogonic stages of P. berghei parasites in vitro independent of their role on mosquito physiology.
Our results show that whereas ivermectin does not affect the parasite's parasitemia, gametocytemia or exflagellation in the mammalian host, several members of the avermectin family of compounds exert a strong inhibitory effect on the generation and development of P. berghei oocysts.
Our results shed light on the action of avermectins against Plasmodium transmission stages and highlight the potential of these compounds to help prevent the spread of malaria.
Harmicines represent hybrid compounds composed of β-carboline alkaloid harmine and cinnamic acid derivatives (CADs). In this paper we report the synthesis of amide-type harmicines and the evaluation ...of their biological activity.
-harmicines
-
and
-harmicines
-
were prepared by a straightforward synthetic procedure, from harmine-based amines and CADs using standard coupling conditions, 1-bis(dimethylamino)methylene-1
-1,2,3-triazolo 4,5-
pyridinium 3-oxid hexafluorophosphate (HATU) and
,
-diisopropylethylamine (DIEA). Amide-type harmicines exerted remarkable activity against the erythrocytic stage of
, in low submicromolar concentrations, which was significantly more pronounced compared to their antiplasmodial activity against the hepatic stages of
. Furthermore, a cytotoxicity assay against the human liver hepatocellular carcinoma cell line (HepG2) revealed favorable selectivity indices of the most active harmicines. Molecular dynamics simulations demonstrated the binding of ligands within the ATP binding site of
Hsp90, while the calculated binding free energies confirmed higher activity of
-harmicines
over their
-substituted analogues
. Amino acids predominantly affecting the binding were identified, which provided guidelines for the further derivatization of the harmine framework towards more efficient agents.
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