TY - JOUR
T1 - Exploring a Tetrahydroquinoline Antimalarial Hit from the Medicines for Malaria Pathogen Box and Identification of its Mode of Resistance as PfeEF2
AU - Laleu, Benoît
AU - Rubiano, Kelly
AU - Yeo, Tomas
AU - Hallyburton, Irene
AU - Anderson, Mark
AU - Crespo-Fernandez, Benigno
AU - Gamo, Francisco Javier
AU - Antonova-Koch, Yevgeniya
AU - Orjuela-Sanchez, Pamela
AU - Wittlin, Sergio
AU - Jana, Gouranga P.
AU - Maity, Bikash C.
AU - Chenu, Elodie
AU - Duffy, James
AU - Sjö, Peter
AU - Waterson, David
AU - Winzeler, Elizabeth
AU - Guantai, Eric
AU - Fidock, David A.
AU - Hansson, Thomas G.
N1 - Funding Information:
MMV was awarded a grant to support the project titled “Exploiting The Pathogen Box: an international Open Source collaboration to accelerate drug development in addressing diseases of poverty.” The project was financed by The World Health Organization (WHO) acting through the Special Programme for Research and Training in Tropical Diseases (TDR). We acknowledge Biobank of Castilla Y Leon and Centro de Transfusiones de Madrid as providers of human red blood cell concentrate for the PRR studies and Sibylle Sax and Christian Scheurer, Swiss TPH for support with the in vitro assays in the panel of P. falciparum strains.
Publisher Copyright:
© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.
PY - 2022/11/18
Y1 - 2022/11/18
N2 - New antimalarial treatments with novel mechanism of action are needed to tackle Plasmodium falciparum infections that are resistant to first-line therapeutics. Here we report the exploration of MMV692140 (2) from the Pathogen Box, a collection of 400 compounds that was made available by Medicines for Malaria Venture (MMV) in 2015. Compound 2 was profiled in in vitro models of malaria and was found to be active against multiple life-cycle stages of Plasmodium parasites. The mode of resistance, and putatively its mode of action, was identified as Plasmodium falciparum translation elongation factor 2 (PfeEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA. The compound maintains activity against a series of drug-resistant parasite strains. The structural motif of the tetrahydroquinoline (2) was explored in a chemistry program with its structure-activity relationships examined, resulting in the identification of an analog with 30-fold improvement of antimalarial asexual blood stage potency.
AB - New antimalarial treatments with novel mechanism of action are needed to tackle Plasmodium falciparum infections that are resistant to first-line therapeutics. Here we report the exploration of MMV692140 (2) from the Pathogen Box, a collection of 400 compounds that was made available by Medicines for Malaria Venture (MMV) in 2015. Compound 2 was profiled in in vitro models of malaria and was found to be active against multiple life-cycle stages of Plasmodium parasites. The mode of resistance, and putatively its mode of action, was identified as Plasmodium falciparum translation elongation factor 2 (PfeEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA. The compound maintains activity against a series of drug-resistant parasite strains. The structural motif of the tetrahydroquinoline (2) was explored in a chemistry program with its structure-activity relationships examined, resulting in the identification of an analog with 30-fold improvement of antimalarial asexual blood stage potency.
KW - biological activity
KW - drug discovery
KW - Malaria
KW - malaria rate of killing
KW - malaria resistance
KW - PfeEF2
UR - https://www.scopus.com/pages/publications/85139608186
U2 - 10.1002/cmdc.202200393
DO - 10.1002/cmdc.202200393
M3 - Article
C2 - 36129427
AN - SCOPUS:85139608186
SN - 1860-7179
VL - 17
JO - ChemMedChem
JF - ChemMedChem
IS - 22
M1 - e202200393
ER -
