Peptides as a Therapeutic Alternative Against Leishmaniasis: A Scoping Review.

Leishmaniasis is a neglected tropical disease with high global health and socioeconomic burden, particularly in low-income regions where current treatments remain limited by high toxicity, cost, and increasing resistance. Antimicrobial peptides (AMPs), small bioactive molecules with broad-spectrum activity and low propensity for resistance, have emerged as promising therapeutic candidates. This scoping review aimed to map the existing literature on AMPs with anti-leishmanial activity, updating and expanding upon previous reviews. Following the PRISMA-ScR framework, we systematically searched for primary research articles assessing natural and synthetic peptides through in vitro or in vivo approaches. Seventy-nine studies met eligibility criteria, evaluating 231 unique peptides against multiple Leishmania species. Most investigations were in vitro, particularly on L. major promastigotes and amastigotes. Synthetic and bioengineered peptides demonstrated superior efficacy and selectivity compared with natural peptides, in some cases achieving selectivity indices exceeding 6000. Mechanistic studies revealed that AMPs act primarily through parasite membrane disruption, but also by inducing apoptosis-like processes and modulating host immune responses. Despite their promise, several challenges remain, including peptide instability in physiological conditions, proteolytic degradation, and limited in vivo validation. Advances in chemical modifications and nanocarrier-based delivery systems show potential to overcome these barriers. In conclusion, AMPs represent a compelling avenue for leishmaniasis therapy, especially for cutaneous forms of the disease. However, further studies, particularly in vivo, are critical to translate preclinical findings into clinical application.