Drug discovery in leishmaniasis using protein lipidation as a target

TY - JOUR

T1 - Drug discovery in leishmaniasis using protein lipidation as a target

AU - Brannigan, James A.

AU - Wilkinson, Anthony J.

N1 - Funding Information: This work was funded by earlier grants from the MRC and the Wellcome Trust. Our current Leishmania work is supported as part of an RCUK GCRF grant (MR/P027989/1) ‘A Global Network for Neglected Tropical Diseases’. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - The leishmaniases are infectious diseases caused by a number of species of obligate intracellular protozoa of the genus Leishmania with disease manifesting as cutaneous, mucocutaneous and visceral forms. Despite being endemic in more than 80 countries and its being the cause of high morbidity and mortality, leishmaniasis remains a neglected tropical disease. Chemotherapy is the frontline treatment, but drugs in current use suffer from toxic side effects, difficulties in administration and extended treatment times — moreover, resistance is emerging. New anti-leishmanial drugs are a recognised international priority. Here, we review investigations into N-myristoyltransferase (NMT) as a potential drug target. NMT catalyses the co-translational transfer of a C14 fatty acid from myristoyl-CoA onto the N-terminal glycine residue of a significant subset of proteins in eukaryotic cells. This covalent modification influences the stability and interactions of substrate proteins with lipids and partner proteins. Structure-guided development of new lead compounds emerging from high-throughput screening campaigns targeting Leishmania donovani NMT has led to the discovery of potent inhibitors which have been used to gain insights into the role of protein myristoylation in these parasites and to validate NMT as a drug target.

AB - The leishmaniases are infectious diseases caused by a number of species of obligate intracellular protozoa of the genus Leishmania with disease manifesting as cutaneous, mucocutaneous and visceral forms. Despite being endemic in more than 80 countries and its being the cause of high morbidity and mortality, leishmaniasis remains a neglected tropical disease. Chemotherapy is the frontline treatment, but drugs in current use suffer from toxic side effects, difficulties in administration and extended treatment times — moreover, resistance is emerging. New anti-leishmanial drugs are a recognised international priority. Here, we review investigations into N-myristoyltransferase (NMT) as a potential drug target. NMT catalyses the co-translational transfer of a C14 fatty acid from myristoyl-CoA onto the N-terminal glycine residue of a significant subset of proteins in eukaryotic cells. This covalent modification influences the stability and interactions of substrate proteins with lipids and partner proteins. Structure-guided development of new lead compounds emerging from high-throughput screening campaigns targeting Leishmania donovani NMT has led to the discovery of potent inhibitors which have been used to gain insights into the role of protein myristoylation in these parasites and to validate NMT as a drug target.

KW - Leishmaniasis inhibitor discovery

KW - N-myristoyltransferase

KW - Neglected tropical disease

KW - Protein structure

UR - http://www.scopus.com/inward/record.url?scp=85118476776&partnerID=8YFLogxK

U2 - 10.1007/s12551-021-00855-0

DO - 10.1007/s12551-021-00855-0

M3 - Review article

AN - SCOPUS:85118476776

SN - 1867-2450

VL - 13

SP - 1139

EP - 1146

JO - Biophysical Reviews

JF - Biophysical Reviews

ER -