AN3661, an Antimalarial Agent, is a PfCPSF3 Inhibitor

AN3661, an Antimalarial Agent, is a PfCPSF3 Inhibitor

Cleavage and polyadenylation specificity factor (CPSF) is relevant to the cleavage of the 3′ signaling region from a newly synthesized pre-messenger RNA (pre-mRNA) molecule. Specifically, it is in the process of gene transcription. It is the first protein to bind to the signal region near the pre-mRNA cleavage site. Besides, poly (a) tails are added via polynucleotide adenylate transferase. Despite various measures taken to curb the spread of malaria, malaria remains an important infectious disease in the world. Moreover, the challenges of malaria control and elimination include widespread drug resistance in Plasmodium falciparum, the deadliest human parasite. Furthermore, there is resistance to most artemisinin-based combination therapy partners. Benzo boron ring compounds are boron-containing compounds, which show effective activity to a variety of infectious pathogens. AN3661, a potent antimalarial lead compound, targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue subunit 3 (PfCPSF3).

AN3661 an Antimalarial Agent is a PfCPSF3 Inhibitor 2020 06 09 - AN3661, an Antimalarial Agent, is a PfCPSF3 Inhibitor

AN3661 targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue subunit 3 (PfCPSF3).

How does AN3661 work on the target? Let’s study it together. In the beginning, AN3661 is a potent antimalarial lead compound and targets PfCPSF3. Meanwhile, AN3661 inhibits Plasmodium falciparum laboratory-adapted strains, Ugandan field isolates, and murine P. berghei and P. falciparum infections.

In addition, AN3661 is active at nanomolar (IC50=20-56 nM) concentrations against P. falciparum laboratory strains known to be sensitive (3D7) or resistant (W2, Dd2, K1, HB3, FCR3 and TM90C2B). Nonetheless, AN3661 is similarly active in ex vivo studies of fresh Ugandan field isolates (mean ex vivo IC50=64 nM). Importantly, AN3661 shows minimal cytotoxicity against mammalian cell lines, with the CC50 60.5 μM against Jurkat cells, and all other CC50 values greater than the highest concentrations tested (25 μM or above). Particularly, AN3661 inhibits the stability of P. falciparum transcripts.

Last but not the least, AN3661 inhibits murine P. berghei infections with ED90 (4 days) 0.34 mg/kg. By orally AN3661 for 4 days, beginning on the third day of infection, the ED90 4 days after initiation of treatment is 0.57 mg/kg.

All in all, AN3661, a potent antimalarial lead compound, is a PfCPSF3 Inhibitor.

References:

 Sonoiki E, et al. Nat Commun. 2017;8:14574. Published 2017 Mar 6.

 

 

 

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