Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

Abstract

The story of antimalarials as antinflammatory drugs dates back few centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, the molecular mechanisms of action have been partly clarified.The inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells. In addition, chloroquine is also as a potent inhibitor of autophagy, providing another possible explanation of its antinflammatory action. However, much attention has been recently devoted to the action of antimalarials on the so-called cGAS-STING pathway deputed to the sensing of nucleic acid and to the production of type 1 interferons. This pathway is a fundamental mechanism for host defence, since it is able to detect microbial DNA and RNA and induce the immune response that will lead to the production of interferons. Of note, genetic defects in disposal of nucleic acids lead to inappropriate activation of the cGAS-STING pathway and inflammation. These disorders, named type I interferonopathies, represent a valuable model to study the antinflammatory potential of antimalarials.We will discuss possible development of antimalarials to improve the treatment of type I interferonopathies and, likely multifactorial disorders characterised by interferon inflammation, such as systemic lupus erythematosus.

The Cyclopeptide Astin C Specifically Inhibits the Innate Immune CDN Sensor STING

“…Quinacrine (QC), a previously identified inhibitor of the cGAS-STING pathway, was included in this study as a control. Consistent with the findings of a previous study (An et al, 2015;Piscianz et al, 2018), QC showed similar IC 50 values in MEFs and IMR-90 cells (6.36 ± 5.80 and 12.18 ± 1.52 mM, respectively). Moreover, astin C did not affect the expression of Il6 mRNA induced upon treatment with TLR agonists poly(I:C) (added into culture medium), lipopolysaccharide (LPS), or R837 ( Figure S1E).…”

“…*p < 0.05 and **p < 0.01. See also Figures S1-S3 and Table S1. to attenuate cGAS activity and have been applied to improve the treatment of type I interferonopathies (An et al, 2015;Piscianz et al, 2018). In addition, H151 was recently characterized as a potent and covalent small-molecular inhibitor of STING (Haag et al, 2018).…”

Higher interferon score and normal complement levels may identify a distinct clinical subset in children with systemic lupus erythematosus

“…Indeed, drugs acting on the IFN pathway are increasingly used for interferonopathies treatment [48,49]. The more listed are antimalarials, old drugs acting on the sensing of nucleic acids in lysosomes and, according to recent findings, on the activation of cGAS enzyme, the principal inducer of type I IFN signalling [50].…”

STING modulators: Predictive significance in drug discovery

“…For instance, RU.521, PF-06928215 and suramin were found to be high-affinity inhibitors of cGAS [149,150]. Interestingly, a few antimalarial drugs, including quinacrine and chloroquine, were also reported to dismiss the activity of cGAS [151,152]. Moreover, disrupting the degradation and expression of STING may provide new insight into the development of small molecular modulators of STING activity.…”