Identification of a New Chemical Class of Antimalarials

The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with half-maximal inhibitory concentration (IC50) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all 3 asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials. ACT-213615 is orally bioavailable in mice, exhibits activity in the murine Plasmodium berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model. ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potentia

The illusion of control drives bet size and reward anticipation in pathological and recreational gamblers

Disordered gambling is the first-ever disorder classified as a behavioural addiction, offering a unique model to study addiction mechanisms in the absence of neurotoxic effects from substances. Previous research suggests that maladaptive reward processing and altered perceptions of control may be key drivers in the development and persistence of gambling behaviour. However, the mechanisms that underlie this association of reward processing and perception of control with gambling are not well understood. In this study, we tested 45 pathological and 45 recreational gamblers using a naturalistic slot machine task, which manipulated reward magnitude and illusion of control in a 2x2 factorial design. We also used a computational reinforcement learning model to examine differences in reward and control processing between addicted and recreational gamblers. Our findings suggest that reward and control have distinct effects on gambling behaviour, with reward magnitude primarily influencing bet behaviour, while illusions of control additionally influence the anticipation of winning. This distortion of expected odds due to an illusion of control may drive continued gambling despite unfavourable outcomes and enhanced risk-taking. Moreover, the illusion of control differentially affected pathological and recreational gamblers and may thus provide a window into the nature of risk-taking across gamblers

Identification of a new chemical class of antimalarials

The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with IC(50) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all three asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials.ACT-213615 is orally bioavailable in mice, exhibits activity in the murine P. berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model.ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potentia

UV-triggered affinity capture identifies interactions between the Plasmodium falciparum multidrug resistance protein 1 (PfMDR1) and antimalarial agents in live parasitized cells

A representative of a new class of potent antimalarials with an unknown mode of action was recently described. To identify the molecular target of this class of antimalarials, we employed a photo-reactive affinity capture method to find parasite proteins specifically interacting with the capture compound in living parasitized cells. The capture reagent retained the antimalarial properties of the parent molecule (ACT-213615) and accumulated within parasites. We identified several proteins interacting with the capture compound and established a functional interaction between ACT-213615 and PfMDR1. We surmise that PfMDR1 may play a role in the antimalarial activity of the piperazine-containing compound ACT-213615