Repurposing sirolimus as a single and combination therapy for malaria: in silico, in vivo and pharmacokinetic studies

Malaria remains endemic in Africa, with emerging reports indicating resistance of the causative agent, Plasmodium spp., to Artemisinin Combination Therapies (ACT) approved for malaria treatment by the World Health Organization (WHO). This study aimed to determine the efficacy of Sirolimus, an immunosuppressive, antineoplastic agent as a repurposed drug for treating malaria and study the pharmacokinetic interactions of Sirolimus with dihydroartemisinin, a component of ACT. In silico molecular docking studies were conducted using seven Plasmodium protein targets to evaluate the binding affinity of Sirolimus compared to reference antimalarials. In vivo suppressive and curative tests were performed using Plasmodium berghei-infected mice. Pharmacokinetic studies assessed the effect of Sirolimus on dihydroartemisinin parameters. Sirolimus had a better binding affinity than the reference compounds on almost all the target proteins. Sirolimus significantly (p < 0.01) suppressed parasite replication more than Artemether. However, mice treated with only sirolimus 72 h after infection showed little reduction in the percentage of parasitemia. Percent parasite reduction by artemether, sirolimus, and coadministration of sirolimus with artemether were 75.35 ± 3.48, 38.68 ± 2.98 and 80.91 ± 6.23, respectively as against that of distilled water which was 4.76 ± 2.57. Also, co-administration of Sirolimus with Artemether affected the pharmacokinetics profile of dihydroartemisinin. The result suggests that Sirolimus possesses suppressive antiplasmodial potential particularly when administered early in infection, and can be combined with Artemether to increase the curative activity of the latter.