Repurposing the Antibacterial Agents Peptide 19-4LF and Peptide 19-2.5 for Treatment of Cutaneous Leishmaniasis
The lack of safe and cost-effective treatments against leishmaniasis highlights the urgent need to develop improved leishmanicidal agents. Antimicrobial peptides (AMPs) are an emerging category of therapeutics exerting a wide range of biological activities such as anti-bacterial, anti-fungal, anti-p...
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| Main Authors: | , , , , , , , , , |
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| Format: | Book |
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MDPI AG,
2022-11-01T00:00:00Z.
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| Summary: | The lack of safe and cost-effective treatments against leishmaniasis highlights the urgent need to develop improved leishmanicidal agents. Antimicrobial peptides (AMPs) are an emerging category of therapeutics exerting a wide range of biological activities such as anti-bacterial, anti-fungal, anti-parasitic and anti-tumoral. In the present study, the approach of repurposing AMPs as antileishmanial drugs was applied. The leishmanicidal activity of two synthetic anti-lipopolysaccharide peptides (SALPs), so-called 19-2.5 and 19-4LF was characterized in <i>Leishmania major</i>. In vitro, both peptides were highly active against intracellular <i>Leishmania major</i> in mouse macrophages without exerting toxicity in host cells. Then, q-PCR-based gene profiling, revealed that this activity was related to the downregulation of several genes involved in drug resistance (<i>yip1</i>), virulence (<i>gp63</i>) and parasite proliferation (<i>Cyclin 1</i> and <i>Cyclin 6</i>). Importantly, the treatment of BALB/c mice with any of the two AMPs caused a significant reduction in <i>L. major</i> infective burden. This effect was associated with an increase in Th1 cytokine levels (<i>IL-12p35</i>, <i>TNF-α</i>, and <i>iNOS</i>) in the skin lesion and spleen of the <i>L. major</i> infected mice while the Th2-associated genes were downregulated (<i>IL-4</i> and <i>IL-6</i>). Lastly, we investigated the effect of both peptides in the gene expression profile of the P2X7 purinergic receptor, which has been reported as a therapeutic target in several diseases. The results showed significant repression of <i>P2X7R</i> by both peptides in the skin lesion of <i>L. major</i> infected mice to an extent comparable to that of a common anti-leishmanial drug, Paromomycin. Our in vitro and in vivo studies suggest that the synthetic AMPs 19-2.5 and 19-4LF are promising candidates for leishmaniasis treatment and present P2X7R as a potential therapeutic target in cutaneous leishmaniasis (CL). |
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| Item Description: | 10.3390/pharmaceutics14112528 1999-4923 |