Repurposing Lansoprazole and Posaconazole to treat Leishmaniasis: Integration of in vitro testing, pharmacological corroboration, and mechanisms of action

Abstract

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.

Drug Reprofiling: A Prospective Approach to Battle Chronic Ailments

“…Posaconazole and Lansoprazole are two new antileishmanial medications that have previously received FDA approval for use in various conditions, and they both put forth plausible mechanisms of action for their antileishmanial effectiveness. 24…”

“…Posaconazole and Lansoprazole are two new antileishmanial medications that have previously received FDA approval for use in various conditions, and they both put forth plausible mechanisms of action for their antileishmanial effectiveness. 24 Due to their high mortality rates and multidrug resistance (MDR), Klebsiella pneumoniae poses a hazard to healthcare globally. DeSarno et al investigated the possibility of treating resistant K. pneumoniae strains by combining zidovudine (AZT) and an already-approved antibiotic.…”

Structural Relationships to Efficacy for Prazole‐Derived Antivirals

“…The second group of compounds (4-9) is biphenyl based, with meta-substitutions on the distal ring. These are nitrile (4, 9), methyl acetate (5,8), carboxy (6), and tetrazole (7). Compounds 8 and 9 additionally substitute hydrogen for methyl at R 2 .…”

“…They also show moderate impact in the PTAP pocket (pink) and the vestigial active site (teal), and only mild impact in the beta-hairpin. Many of the larger derivatives (4,5,7,8,9,10,11,13,16) show minimal attachment, either reflective of limited conversion or poor solubility. Those larger derivatives that appear to show significant attachment (6,12,14,17,18) again have a strong impact in the prazole-binding site but show a significant loss at the beta-hairpin extension, rather than the PTAP pocket, indicating that they may be more strongly block Ub binding.…”

“…[2] Additionally, the conversion to the active species is acidcatalyzed, leading to the accumulation of active drugs at the desired site of action. [2] The ability to administer a prodrug form of the compound, which is contextually activated, together with the formation of covalent adducts with protein cysteine residues, have recently made prazoles an attractive class for anticancer, [3,4] antiprotozoal, [5] antibiotic, [6] and antiviral applications. [7][8][9][10] Beyond these, a large-scale target trial emulation study of Alzheimer's disease data identified two prazoles in the top five candidates repurposable for Alzheimer's disease.…”