Structurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections

PLoS Neglected Tropical Diseases
Evan CraigPeter E Kima

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 a...Continue Reading

References

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Citations

May 15, 2020·Cellular Microbiology·Sandrine CojeanVanessa Lievin-Le Moal
Jul 30, 2020·PLoS Neglected Tropical Diseases·Sandrine CojeanVanessa Lievin-Le Moal
Jul 1, 2020·Frontiers in Cellular and Infection Microbiology·Natalia Rocha NadaesLucia Helena Pinto-da-Silva
May 12, 2020·Frontiers in Microbiology·Lalita PriyamvadaPanayampalli S Satheshkumar
Jul 3, 2021·The Journal of Antimicrobial Chemotherapy·Sébastien PomelPhilippe M Loiseau

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Methods Mentioned

BETA
Assay
ELISA
light microscopy
ELISAs
dissection
column chromatography

Software Mentioned

ImageJ
GraphPad Prism
Click
Excel

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