Title:Antileishmanial Drug Development: A Review of Modern Molecular Chemical Tools and Research Strategies
Volume: 28
Issue: 31
Author(s): Pavan K. Mantravadi, Anutthaman Parthasarathy and Karunakaran Kalesh*
Affiliation:
- Department of Chemistry, Durham University, Lower Mount Joy, South Road, Durham DH1 3LE,United Kingdom
Keywords:
Leishmaniasis, phenotypic screening, target-based screening, CRISP/Cas9, cosmid library, proteasome,
N-myristoylation, cyclin-dependent kinase.
Abstract: Leishmaniasis, a complex disease caused by at least 20 species of unicellular
parasites of the genus Leishmania, disproportionately affects impoverished regions of
about 90 tropical and sub-tropical countries. Currently available antileishmanial therapies,
particularly for visceral leishmaniasis, are severely limited, with treatment outcome
depending on many factors, including the immune status of the patient, comorbidities,
malnutrition, and socio-economic conditions in the patient’s geographic location. There
is an urgent need for new therapeutics, particularly new effective oral drugs, for visceral
leishmaniasis. Despite the availability of the Leishmania genome sequence information
and significant research into the biology of the parasites, antileishmanial drug development
is hampered by the lack of knowledge about druggable targets in the parasite and
difficulties in identifying the molecular targets of compounds that show activity. In this
context, we analyzed recent progress in antileishmanial drug development programs,
which take advantage of different powerful approaches, such as high-throughput screening
of compound libraries, recent developments in genetic methods for assessing essentiality
of parasite genes, and chemical, genetic, and proteomics-based target discovery
and target validation methods.