Open AccessStructurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections
Author(s) -
Evan Craig,
Charles-Eugene Huyghues-Despointes,
Chun Jiang Yu,
Emma Handy,
Jason K. Sello,
Peter E. Kima
Publication year - 2017
Publication title -
plos neglected tropical diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.99
H-Index - 135
eISSN - 1935-2735
pISSN - 1935-2727
DOI - 10.1371/journal.pntd.0005556
Subject(s) - leishmania , leishmania mexicana , amastigote , axenic , biology , leishmaniasis , leishmania major , potency , parasite hosting , in vitro , immunology , biochemistry , genetics , bacteria , world wide web , computer science
In infected mammalian cells, Leishmania parasites reside within specialized compartments called parasitophorous vacuoles (LPVs). We have previously shown that Retro-2, a member of a novel class of small retrograde pathway inhibitors caused reduced LPV sizes and lower parasite numbers during experimental L . mexicana sp. infections. The purpose of this study was to determine if structural analogs of Retro-2 cycl reported to have superior potency in the inhibition of retrograde pathway-dependent phenomena ( i . e ., polyomavirus cellular infection by polyomavrius and Shiga toxin trafficking in cells) are also more effective than the parent compound at controlling Leishmania infections. In addition to their effects on LPV development, we show that two optimized analogs of Retro-2 cycl , DHQZ 36 and DHQZ 36.1 limit Leishmania amazonensis infection in macrophages at EC 50 of 13.63+/-2.58μM and10.57+/-2.66μM, respectively, which is significantly lower than 40.15μM the EC 50 of Retro-2 cycl . In addition, these analogs caused a reversal in Leishmania induced suppression of IL-6 release by infected cells after LPS activation. Moreover, we show that in contrast to Retro-2 cycl that is Leishmania static, the analogs can kill Leishmania parasites in axenic cultures, which is a desirable attribute for any drug to treat Leishmania infections. Together, these studies validate and extend the published structure-activity relationship analyses of Retro-2 cycl .