Abstract
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-2cycl 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-2cycl, DHQZ 36 and DHQZ 36.1 limit Leishmania amazonensis infection in macrophages at EC50 of 13.63+/-2.58μM and10.57+/-2.66μM, respectively, which is significantly lower than 40.15μM the EC50 of Retro-2cycl. 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-2cycl 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-2cycl.
Highlights
Leishmaniasis is a disease with clinical presentations that range from cutaneous lesions to visceral disease
Over 12 million people worldwide are infected by Leishmania parasites and many more are at risk of being infected
Leishmania parasites live in intracellular compartments called parasitophorous vacuoles (LPVs)
Summary
Leishmaniasis is a disease with clinical presentations that range from cutaneous lesions to visceral disease. A few studies have shown that some molecules that are otherwise localized to or associated with secretory pathway compartments are displayed on LPVs as well [2][3] These molecules include the endoplasmic reticulum resident, calnexin and several soluble N-ethylmaleimide-sensitive fusion attachment protein receptors (SNAREs) such as syntaxin 5 (Stx5), 18 and sec22b that mediate the fusion of early secretory pathway vesicles [4]. These SNARE molecules were shown to be functionally relevant to LPV biogenesis with evidence that expression of dominant negative variants or when their protein levels in cells were knocked down, the result was that smaller LPVs developed that harbored much fewer L. mexicana complex (L. pifanoi and L. amazonensis) parasites [3].
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