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Cipargamin: Biocatalysis in the Discovery and Development of an Antimalarial Drug
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Thomas Ruch, Elina Siirola, Radka Snajdrova
The ongoing challenge of malaria medication is the constantly developing drug resistance profile of the malaria parasites (Greenwood et al., 2014). Early malaria drugs chloroquine and sulphadoxinepyrimethamine both lost their efficiency due to the build-up of resistance (Wells et al., 2015). Although artemisinin and its combination therapies were developed to substitute the early drugs and to battle the disease, the recent discovery of artemisinin resistant parasites in South-East Asia has raised concerns again (Imwong et al., 2017). Importantly, despite the success of artemisinin, antimalarial research programs have been continued for developing malaria drugs with different and novel mode of actions (Hooft van Huijsduijnen et al., 2018; Wells et al., 2015). One of the new drug candidates in clinical development for the treatment of malaria is Cipargamin (KAE609, NITD609) (Barquero et al., 2015; Yeung, 2017). This new class of spiroindolones (Yeung et al., 2010) inhibits the growth of Plasmodium-parasites through the novel mechanism of inhibition of a P-type cation-transporter ATPase. Inhibition of this Na+ pump (efflux of Na+, influx of H+) causes fatal disruption of Na+ homeostasis in Plasmodium (Turner et al., 2016). Cipargamin is a chiral compound with two stereogenic centers of which the 1R, 3S enantiomer showed best pharmacokinetic profile (Scheme 15.1) (Sibley et al., 2012; Yeung et al., 2010). Structure of Cipargamin, KAE609, (1R,3S)-5′,7-Dichloro-6-fluoro-3-methyl-spiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,3′-indoline]-2′-one.
Antimalarial drugs: what’s new in the patents?
Published in Expert Opinion on Therapeutic Patents, 2023
Elizabeth A. Lopes, Maria M. M. Santos, Mattia Mori
Drug resistance to the available malaria treatments has emerged and is slowing down malaria eradication. The mechanisms of drug resistance developed by the parasite are not completely characterized, especially for P. vivax and P. malariae. In P. falciparum, mutations in some genes, as pfk13 and pfcrt, have been shown to be responsible for artemisinin and chloroquine resistance, respectively. Other resistance mechanisms involve enzymatic degradation and drug-related issues including drug efflux, modification, and alteration to the drug target [9–11]. As drug resistance represents the major drawback of current antimalarial treatment options, novel drugs able to overcome this issue are urgently needed. A virtuous example of antimalarial drug discovery is represented by the clinical candidate cipargamin, which is currently under phase III clinical trials and has a new mechanism of action. Cipargamin targets not only the erythrocytic stage, as well as the sexual malaria parasite life cycle stage by inhibiting the sodium efflux pump PfATP4 [12]. It is worth noting that targeting the sexual stage reduces the number of gametocytes able to infect the mosquito vector that bites the infected host [13].
Pharmacotherapy for artemisinin-resistant malaria
Published in Expert Opinion on Pharmacotherapy, 2021
Erik Koehne, Ayola Akim Adegnika, Jana Held, Andrea Kreidenweiss
Ganaplacide (KAF156), an imidazolpiperazine, and cipargamin (KAE609), a spiroindolone, are new antimalarial compounds currently in clinical development for the treatment of uncomplicated malaria and are currently in ongoing phase 2 trials. Ganaplacide and cipargamin were shown to be effective in vitro against P. falciparum with IC50s of 6–17.4 nM and 0.5 to 1.4 nM, respectively [119,120]. Currently, data from four published clinical trials exist for ganaplacide including a malaria challenge study [121–124]. Ganaplacide was well-tolerated when given at a daily dose of 400 mg for 3 days and a single dose of 800 mg, and had an overall 28-day cure rate of 67% in a small number of adults with uncomplicated P. vivax or P. falciparum malaria after single-dose administration [122]. Ganaplacide is currently developed in combination with lumefantrine [125] for a short treatment course. Data from seven clinical trials show cipargamin to be well-tolerated in healthy volunteers and in patients, however, there are some safety concerns in regard to liver function test abnormalities [126] A recently published malaria challenge trial reports antiplasmodial activity of a single dose, however liver safety signals appeared [127]. In a phase 2 trial done in Thailand, twenty-one patients with uncomplicated P. falciparum and P. vivax malaria were treated with a dose of 30 mg per day for three days and showed a parasite clearance half-life of less than 1 hour, that is even faster than artesunate [122,128]. Cipargamin is a promising candidate for a once-daily regimen.
Malaria transmission blocking compounds: a patent review
Published in Expert Opinion on Therapeutic Patents, 2022
Sara Consalvi, Chiara Tammaro, Federico Appetecchia, Mariangela Biava, Giovanna Poce
To date, there are three available antimalarial drugs targeting different stages of transmissions: primaquine (PQ), atovaquone (ATQ) and methylene blue (MB). PQ and MB target the intraerythrocytic gametocyte stages, whereas ATQ is highly active only against the sporogonic ones (inhibits ookinete and oocyst formation) [36–40]. A transmission-specific agent has yet to be approved and the only drug recommended by the WHO for transmission blocking is PQ, which can be administered in association with artemisinin in low to moderate transmission settings. Unfortunately, its use is seriously limited by side effects as it causes hemolytic anemia in glucose-6-phosphate-dehydrogenase (G6PD)-deficient individuals. In the last decade, activity against sexual stages has not been seen exclusively as an added value to schizonticide drugs, and transmission-blocking interventions have been prioritized as a primary objective to achieve malaria elimination. Therefore, there is an increased interest to find drugs active against sexual stages of Plasmodium, and many transmission-blocking agents are currently in clinical [41] and preclinical development [42,43]. Many of them are an outcome of collaborative partnership coordinated by Malaria Medicines Venture (MMV). Interestingly, none of them was developed as a transmission-specific drug, as they were first profiled against asexual stages of plasmodium, and then resulted active against sexual ones (Table 1). Among them, cipargamin (Table 1) is the most advanced candidate with the potential to reduce human-to-mosquito transmission. This drug showed an outstanding potency both against early and late-stage gametocytes and seems to act by inducing an osmotic stability perturbation. Interestingly, it retains a significant activity both against male and female gametocytes of artemisin-resistant parasites [44] and has a dose dependent sporonticidal activity, yielding complete inhibition of oocysts counts at 500 nM. Its effectiveness in inhibiting gametocyte transmissibility was also investigated in healthy volunteers infected with blood-stage P. falciparum after a single-10 mg-oral dose at the day 7 after infection, using an induced blood-stage malaria model. Unfortunately, the study was terminated due to three unexpected abnormalities in the liver function test (LFT). Even though gametocytocidal activity of cipargamin was not assessed, valuable information about the efficacy of this drug in reducing human-to-mosquito transmission was obtained through a direct-membrane feeding assay. Following piperaquine administration, gametocytes were detected in all the patients tested, suggesting that the blood exposure of cipargamin was too low to kill mature gametocytes or prevent their development at the time they reentered circulation. However, no oocysts were detected in any of the mosquito midgut samples and transmission was not detected in any of the subjects. Unfortunately, it was not possible to conclude whether this was due to low gametocyte density or because cipargamin was able to render gametocyte infertile. However, these findings, along with its high potency in inhibiting oocyst development in vitro, support further investigation into its transmission-blocking potential [45].