Ex Vivo Phenotypic Screening of Two Small Repurposing
Drug Collections Identifies Nifuratel as a Potential New Treatment
against Visceral and Cutaneous Leishmaniasis
posted on 2021-06-11, 13:34authored byBárbara Domínguez-Asenjo, Camino Gutiérrez-Corbo, María Álvarez-Bardón, Yolanda Pérez-Pertejo, Rafael Balaña-Fouce, Rosa M. Reguera
Leishmaniases
are vector-borne neglected diseases caused by single-celled
parasites. The search for new antileishmanial drugs has experienced
a strong boost thanks to the application of bioimaging to phenotypic
screenings based on intracellular amastigotes. Mouse splenic explants
infected with fluorescent strains of Leishmania are
proven tools of drug discovery, where hits can be easily transferred
to preclinical in vivo models. We have developed a two-staged platform
for antileishmanial drugs. First, we screened two commercial collections
of repurposing drugs with a total of 1769 compounds in ex vivo mouse
splenocytes infected with an infrared emitting Leishmania
infantum strain. The most active and safest compounds were
scaled-up to in vivo models of chronic Leishmania donovani visceral leishmaniasis and Leishmania major cutaneous
leishmaniasis. From the total of 1769 compounds, 12 hits with selective
indices >35 were identified, and 4 of them were tested in vivo
in
a model of L. donovani visceral leishmaniasis.
Nifuratel, a repurposed synthetic nitrofuran, when administered orally
at 50 mg/kg bw once or twice a day for 10 days, caused >80% reduction
in the parasitic load. Furthermore, the intralesional administration
of nifuratel in a model of cutaneous leishmaniasis by L. major produced the parasitological cure. From the previous results we
have deduced the great capacity of mouse splenic explants to identify
new hits, a model which could be easily transferred to in vivo models,
as well as the potential use of nifuratel as an alternative to the
current treatment of cutaneous leishmaniasis.