Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase.

Autor:	Mina JGM; Departments of Chemistry, University of Durham, Science Laboratories, South Road, Durham DH1 3LE, United Kingdom., Charlton RL; Departments of Chemistry, University of Durham, Science Laboratories, South Road, Durham DH1 3LE, United Kingdom.; Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Rio de Janeiro, Brazil., Alpizar-Sosa E; Department of Biosciences, University of Durham, South Road, Durham DH1 3LE, United Kingdom.; Wellcome Centre for Integrative Parasitology and Glasgow Polyomics, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom., Escrivani DO; Departments of Chemistry, University of Durham, Science Laboratories, South Road, Durham DH1 3LE, United Kingdom.; Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Rio de Janeiro, Brazil., Brown C; Departments of Chemistry, University of Durham, Science Laboratories, South Road, Durham DH1 3LE, United Kingdom., Alqaisi A; Department of Biosciences, University of Durham, South Road, Durham DH1 3LE, United Kingdom.; Department of Biology, College of Science, University of Baghdad, Baghdad 10071, Iraq., Borsodi MPG; Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Rio de Janeiro, Brazil., Figueiredo CP; School of Pharmacy, Universidade Federal do Rio de Janeiro, 21944-590 Rio de Janeiro, Rio de Janeiro, Brazil., de Lima EV; School of Pharmacy, Universidade Federal do Rio de Janeiro, 21944-590 Rio de Janeiro, Rio de Janeiro, Brazil., Dickie EA; Wellcome Centre for Integrative Parasitology and Glasgow Polyomics, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom., Wei W; Department of Biosciences, University of Durham, South Road, Durham DH1 3LE, United Kingdom., Coutinho-Silva R; Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Rio de Janeiro, Brazil., Merritt A; LifeArc, Open Innovation Campus, Stevenage SG1 2FX, United Kingdom., Smith TK; BSRC, Schools of Biology and Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, United Kingdom., Barrett MP; Wellcome Centre for Integrative Parasitology and Glasgow Polyomics, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom., Rossi-Bergmann B; Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Rio de Janeiro, Brazil., Denny PW; Department of Biosciences, University of Durham, South Road, Durham DH1 3LE, United Kingdom., Steel PG; Departments of Chemistry, University of Durham, Science Laboratories, South Road, Durham DH1 3LE, United Kingdom.
Jazyk:	angličtina
Zdroj:	ACS infectious diseases [ACS Infect Dis] 2021 Jan 08; Vol. 7 (1), pp. 47-63. Date of Electronic Publication: 2020 Dec 08.
DOI:	10.1021/acsinfecdis.0c00546
Abstrakt:	Current chemotherapeutics for leishmaniasis have multiple deficiencies, and there is a need for new safe, efficacious, and affordable medicines. This study describes a successful drug repurposing approach that identifies the over-the-counter antihistamine, clemastine fumarate, as a potential antileishmanial drug candidate. The screening for inhibitors of the sphingolipid synthase (inositol phosphorylceramide synthase, IPCS) afforded, following secondary screening against Leishmania major (Lmj) promastigotes, 16 active compounds. Further refinement through the dose response against Lmj IPCS and intramacrophage L. major amastigotes identified clemastine fumarate with good activity and selectivity with respect to the host macrophage. On target engagement was supported by diminished sensitivity in a sphingolipid-deficient L. major mutant (Δ Lmj LCB2) and altered phospholipid and sphingolipid profiles upon treatment with clemastine fumarate. The drug also induced an enhanced host cell response to infection indicative of polypharmacology. The activity was sustained across a panel of Old and New World Leishmania species, displaying an in vivo activity equivalent to the currently used drug, glucantime, in a mouse model of L. amazonensis infection. Overall, these data validate IPCS as an antileishmanial drug target and indicate that clemastine fumarate is a candidate for repurposing for the treatment of leishmaniasis.
Databáze:	MEDLINE
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