Applicability of Redirecting Artemisinins for New Targets

Abstract

Employing new therapeutic indications for drugs that are already approved for human use has obvious advantages, including reduced costs and timelines, because some routine steps of drug development and regulation are not required. This work concentrates on the redirection of artemisinins (ARTS) that already are approved for clinical use, or investigated, for malaria treatment. Several mechanisms of action are suggested for ARTS, among which only a few have been successfully examined in vivo, mainly the induction of oxidant stress and anti-inflammatory effects. Despite these seemingly contradictory effects, ARTS are proposed for repurposing in treatment of inflammatory disorders and diverse types of diseases caused by viral, bacterial, fungal, and parasitic infections. When pathogens are treated the expected outcome is diminution of the causative agents and/or their inflammatory damage. In general, repurposing ARTS is successful in only a very few cases, specifically when a valid mechanism can be targeted using an additional therapeutic agent and appropriate drug delivery. Investigation of repurposing should include optimization of drug combinations followed by examination in relevant cell lines, organoids, and animal models, before moving to clinical trials.

Keywords: bacterial infections; cancer; microbiota; parasites; repurposing artemisinin; viral infections.

Figure 1

Structures of artemisinin and some of its derivatives.

Figure 2

Artesunate alignment in its binding to SARS‐CoV‐2 spike protein. Artesunate aligned in the binding interface of the S‐protein (viral) RBD‐hACE2 complex. Shown in cyan is the S‐Protein RBD and in green hACE2 (the human receptor). Artesunate is shown in purple^{[ 63 ]} (permission allocated).

Figure 3

Formulation of artemisone (ART) in lipid micro‐emulsion. Artemisone (ART) shows poor water solubility (89 ng mL⁻¹) and decomposition in aqueous environment (pH‐dependent). The solubility of the drug is greatly increased (∼ ×1000) in the lipid excipients.

Figure 4

Treatment of cutaneous leishmaniasis by artemisone. BALB/c mice were infected subcutaneously on the lower back just above the tail with Leishmania major Friedlin strain (5 × 10⁶ metacyclic promastigotes) as previously described.^{[ 95 ]} Lesions appeared on day 7. Mice were treated twice a day on days 8–11 and 14–17 post‐infection (PI) by spraying artemisone (1 mg per dose). Representative lesions for the control (n = 5) and treated (n = 6) mice on day 25 PI are shown. The average lesion size was (mean±SE) 51.5^±6.6 and 28.1^±3.2 mm² for each group, respectively (p<0.05, Prisme paired T‐test), (Golenser et al. unpublished results). The spraying method is detailed in Zech et al.,^{[ 90 ]} This research conforms to the Hebrew University Animal Ethical Committee guidelines, ethics number MD‐14‐13923‐3.

Figure 5

Gross macroscopic observation of livers of Schistosoma‐infected mice, vehicle or artemisone‐treated. Representative photographs are shown of liver lobes and spleens from male mice infected with schistosomes and then treated with either a placebo (n = 5, upper photographs) or artemisone (n = 5, lower photographs). Mice were treated by gavage at 23–25‐ and 29–31 days post‐infection twice a day, with 40 mg k⁻¹g, in microemulsion. Worm number in the control and drug‐treated mice was 48^±16 and 1.5^±0.4 (p<0.01 by Prism T‐test), respectively. The spleen weights of the control mice were about 20 times higher than that of the treated ones. Formulation and treatment methods are detailed elsewhere.^{[ 89 ]}

Figure 6

Targeting toward applicability.