Recently, a Chinese research team discovered CHMFL-PI4K-127 as a novel Plasmodium falciparum PI(4)K inhibitor, which displayed potent anti-malarial activity against both blood and liver stages of Plasmodium.

Malaria is a life-threatening disease transmitted by mosquitoes. Although artemisinin has greatly reduced the mortality rate for malaria patients, drug resistant malaria infections are still a severe threat to the public health.

Therefore, there is yet a great demand to seek novel chemotypes with new antimalarial mechanisms in order to overcome the drug resistance.

Plasmodium phosphatidylinositol-4-kinase (PI4K) is one of the attractive drug targets, which plays important roles in all stages of the Plasmodium lifecycle.

In this study, LIU Qingsong’s group from Hefei Institutes of Physical Science, Chinese Academy of Sciences and JIANG Lubin’s group from Institute Pasteur of Shanghai, Chinese Academy of Sciences worked together and discovered a novel Plasmodium falciparum PI(4)K inhibitor (CHMFL-PI4K-127) through structure-based drug design.

CHMFL-PI4K-127 exhibited potent activity against PI4K (IC50: 0.9 nM) and 3D7 Plasmodium falciparum (EC50: 25 nM). It also displayed high selectivity against PfPI4K over human lipid and protein kinase.

In addition, CHMFL-PI4K-127 exhibited EC50 values of 23-47 nM against a panel of the drug-resistant strains of P. falciparum.

Furthermore, CHMFL-PI4K-127 exhibited anti-malaria efficacy in both blood stage (80 mg/kg) and liver stage (1 mg/kg) of Plasmodium in infected rodent model through oral administration. The results suggested that the inhibitor might be a new potential drug candidate for malaria.

This work was supported by the National Natural Science Foundation of China, the Youth Innovation Promotion Association of Chinese Academy of Sciences, the Youth Innovation Promotion Association of CAS.

Link to the paper: Discovery of 6′-chloro-N-methyl-5’-(phenylsulfonamido)-[3,3′-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium

Efficacies of CHMFL-PfPI4K-127 in blood stage (left) and liver stage (right) (Image by LIANG Xiaofei)

Contact:

ZHOU Shu

Hefei Institutes of Physical Science (http://english.hf.cas.cn/)

Email: zhous@hfcas.ac.cn