"Redefining Leishmaniasis Therapy: Innovations in Drug Discovery and Vaccine Design".

Abstract

Leishmaniasis remains a major neglected tropical disease that causes substantial morbidity and mortality worldwide, especially in resource-limited regions. Pentavalent antimonials, amphotericin B, miltefosine, pentamidine, and paromomycin are among the medications that continue to dominate the treatment landscape after decades of research. Although these drugs remain clinically effective, significant obstacles such as systemic toxicity, emerging drug resistance, expensive therapy, extended parenteral administration, and restricted accessibility in endemic areas prevent their widespread use. As a result, efforts in drug development and translational research have been revitalized by the demand for safer, more economical, and more effective treatments. Recent developments focus primarily on mechanism-based drug discovery that targets pathways specific to parasites such as proteasomes, kinases, RNA-processing enzymes and subtilisin proteases. Recent efforts have also highlighted mitochondrial targets such as bc1 complex and have been supported by CRISPR/Cas9-based functional genomics and computational approaches for target identification and drug repurposing. These efforts have been enhanced by computational drug repurposing. Promising candidates like LXE408, GSK3494245, DDD853651, PF-429242 and the cytochrome bc1 inhibitor DNDI-6174 have demonstrated promising preclinical or early clinical potential. Innovations in CRISPR-based functional genomics, in silico drug repurposing, and nanotechnology-enabled delivery systems have supported the promising preclinical and early clinical results of novel candidates such as LXE408, GSK3494245, CRK12 inhibitors, and benzoxaboroles (e.g., DNDI-6148). Although vaccine development has progressed considerably, there is still no viable human vaccination against leishmaniasis. Crude whole-parasite formulations have given way to recombinant polyprotein vaccines, viral vectors, DNA vaccines, multi-epitope constructs, nanoparticle-based formulations, virus-like particle vaccines and live-attenuated strains as modern vaccination approaches. While genetically attenuated strains like LmCen-/- have proven significant protection in experimental and veterinary contexts, candidates including LEISH-F1, LEISH-F3+GLA-SE, and ChAd63-KH, Neoleish, GH18-cpLeish and CpG-adjuvant virus-like particle vaccine have demonstrated safety and immunogenicity in early clinical studies. However, vaccine development is still hampered by issues like antigenic diversity, immune evasion by the parasite, and the absence of trustworthy correlates of protection. Overall, combining cutting-edge drug discovery technology with innovative vaccine platforms offers promising opportunities for developing effective therapeutic and preventive strategies for leishmaniasis.