title: Auranofin is an apoptosis-simulating agent with in vitro and in vivo anti-leishmanial activity.
abstract: Cutaneous leishmaniasis remains ignored in therapeutic drug discovery programs worldwide. This is mainly because cutaneous leishmaniasis is frequently a disease of impoverished populations in countries where funds are limited for research and patient care. However, the health burden of individuals in endemic areas mandates readily available, effective, and safe treatments. Of the existing cutaneous leishmaniasis therapeutics, many are growth inhibitory to Leishmania parasites, potentially creating dormant parasite reservoirs that can be activated when host immunity is compromised, enabling the reemergence of cutaneous leishmaniasis lesions or worse spread of Leishmania parasites to other body sites. To accelerate the identification and development of novel cutaneous leishmaniasis therapeutics, we designed an integrated in vitro and in vivo screening platform that incorporated multiple Leishmania life cycles and species and probed a focused library of pharmaceutically active compounds. The objective of this phenotypic drug discovery platform was the identification and prioritization of bona fide cytotoxic chemotypes toward Leishmania parasites. We identified the Food and Drug Administration-approved drug auranofin, a known inhibitor of Leishmania promastigote growth, as a potent cytotoxic anti-leishmanial agent and inducer of apoptotic-like death in promastigotes. Significantly, the anti-leishmanial activity of auranofin transferred to cell-based amastigote assays as well as in vivo murine models. With appropriate future investigation, these data may provide the foundation for potential exploitation of gold(I)-based complexes as chemical tools or the basis of therapeutics for leishmaniasis. Thus, auranofin may represent a prototype drug that can be used to identify signaling pathways within the parasite and host cell critical for parasite growth and survival.
authors: Departments of †Pharmacology and ‡Chemistry, University of Virginia , Charlottesville, Virginia 22908, United States.
authors: Elizabeth R
authors: ER
authors: Sharlow
authors: Stephanie
authors: S
authors: Leimgruber
authors: Samantha
authors: S
authors: Murray
authors: Ana
authors: A
authors: Lira
authors: Richard J
authors: RJ
authors: Sciotti
authors: Mark
authors: M
authors: Hickman
authors: Thomas
authors: T
authors: Hudson
authors: Susan
authors: S
authors: Leed
authors: Diana
authors: D
authors: Caridha
authors: Amy M
authors: AM
authors: Barrios
authors: David
authors: D
authors: Close
authors: Max
authors: M
authors: Grögl
authors: John S
authors: JS
authors: Lazo
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001310:Auranofin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D007891:Leishmania / Q000187:drug effects* / Q000472:pathogenicity; D007896:Leishmaniasis / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D001310:Auranofin