TY - JOUR
T1 - Repurposing Lansoprazole and Posaconazole to treat leishmaniasis
T2 - Integration of in vitro testing, pharmacological corroboration, and mechanisms of action
AU - Gupta, Yash
AU - Goicoechea, Steven
AU - Romero, Jesus G.
AU - Mathur, Raman
AU - Caulfield, Thomas R.
AU - Becker, Daniel P.
AU - Durvasula, Ravi
AU - Kempaiah, Prakasha
N1 - Funding Information:
We thank Dr. Abhy Satoskar (Ohio State University) for graciously providing the L. donovani strain expressing the reporter gene. Authors sincerely thank the Department of Medicine, Loyola University Chicago Stritch School of Medicine for providing the initial funding support for the Drug Discovery Program and Software acquisition.
Publisher Copyright:
© 2022, Taiwan Food and Drug Administration. All rights reserved.
PY - 2022
Y1 - 2022
N2 - Leishmaniasis remains a serious public health problem in many tropical regions of the world. Among neglected tropical diseases, the mortality rate of leishmaniasis is second only to malaria. All currently approved therapeutics have toxic side effects and face rapidly increasing resistance. To identify existing drugs with antileishmanial activity and predict the mechanism of action, we designed a drug-discovery pipeline utilizing both in-silico and in-vitro methods. First, we screened compounds from the Selleckchem Bio-Active Compound Library containing ~1622 FDA-approved drugs and narrowed these down to 96 candidates based on data mining for possible anti-parasitic properties. Next, we completed preliminary in-vitro testing of compounds against Leishmania amastigotes and selected the most promising active compounds, Lansoprazole and Posaconazole. We identified possible Leishmania drug targets of Lansoprazole and Posaconazole using several available servers. Our in-silico screen identified likely Lansoprazole targets as the closely related calcium-transporting ATPases (LdBPK_352080.1, LdBPK_040010.1, and LdBPK_170660.1), and the Posaconazole target as lanosterol 14-alpha-demethylase (LdBPK_111100.1). Further validation showed LdBPK_352080.1 to be the most plausible target based on induced-fit docking followed by long (100ns) MD simulations to confirm the stability of the docked complexes. We present a likely ion channel-based mechanism of action of Lansoprazole against Leishmania calcium-transporting ATPases, which are essential for parasite metabolism and infectivity. The LdBPK_111100.1 interaction with Posaconazole is very similar to the known fungal orthologue. Herein, we present two novel anti-leishmanial agents, Posaconazole and Lansoprazole, already approved by the FDA for different indications and propose plausible mechanisms of action for their antileishmanial activity.
AB - Leishmaniasis remains a serious public health problem in many tropical regions of the world. Among neglected tropical diseases, the mortality rate of leishmaniasis is second only to malaria. All currently approved therapeutics have toxic side effects and face rapidly increasing resistance. To identify existing drugs with antileishmanial activity and predict the mechanism of action, we designed a drug-discovery pipeline utilizing both in-silico and in-vitro methods. First, we screened compounds from the Selleckchem Bio-Active Compound Library containing ~1622 FDA-approved drugs and narrowed these down to 96 candidates based on data mining for possible anti-parasitic properties. Next, we completed preliminary in-vitro testing of compounds against Leishmania amastigotes and selected the most promising active compounds, Lansoprazole and Posaconazole. We identified possible Leishmania drug targets of Lansoprazole and Posaconazole using several available servers. Our in-silico screen identified likely Lansoprazole targets as the closely related calcium-transporting ATPases (LdBPK_352080.1, LdBPK_040010.1, and LdBPK_170660.1), and the Posaconazole target as lanosterol 14-alpha-demethylase (LdBPK_111100.1). Further validation showed LdBPK_352080.1 to be the most plausible target based on induced-fit docking followed by long (100ns) MD simulations to confirm the stability of the docked complexes. We present a likely ion channel-based mechanism of action of Lansoprazole against Leishmania calcium-transporting ATPases, which are essential for parasite metabolism and infectivity. The LdBPK_111100.1 interaction with Posaconazole is very similar to the known fungal orthologue. Herein, we present two novel anti-leishmanial agents, Posaconazole and Lansoprazole, already approved by the FDA for different indications and propose plausible mechanisms of action for their antileishmanial activity.
KW - Drug repurposing
KW - Lansoprazole
KW - Leishmaniasis
KW - Molecular dynamics
KW - Posaconazole
UR - http://www.scopus.com/inward/record.url?scp=85127177417&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127177417&partnerID=8YFLogxK
U2 - 10.38212/2224-6614.3394
DO - 10.38212/2224-6614.3394
M3 - Article
C2 - 35647721
AN - SCOPUS:85127177417
SN - 1021-9498
VL - 30
SP - 128
EP - 149
JO - Journal of Food and Drug Analysis
JF - Journal of Food and Drug Analysis
IS - 1
M1 - 11
ER -