The Stapled AKAP Disruptor Peptide STAD-2 Displays Antimalarial Activity through a PKA-Independent Mechanism

摘要: Drug resistance poses a significant threat to ongoing malaria control efforts. Coupled with lack of vaccine, there is an urgent need for the development new antimalarials novel mechanisms action and low susceptibility parasite drug resistance. Protein Kinase A (PKA) has been implicated as critical regulator pathogenesis in malaria. Therefore, we sought investigate effects disrupted PKA signaling possible strategy inhibition replication. Host activity partly regulated by class proteins called Anchoring Proteins (AKAPs), interaction between HsPKA AKAP can be inhibited stapled peptide Stapled Disruptor 2 (STAD-2). STAD-2 was tested permeability against Plasmodium falciparum blood stage parasites vitro. The compound selectively permeable only infected red cells (iRBC) demonstrated rapid antiplasmodial activity, possibly via iRBC lysis (IC50 ≈ 1 μM). localized within almost immediately post-treatment but showed no evidence direct association PKA, indicating that acts PKA-independent mechanism. Furosemide-insensitive pathways were largely responsible uptake STAD-2. Further, import highly specific evidenced peptides. Selective provides important groundwork peptides potential antimalarials. Such may also offer alternative studying protein-protein interactions pathogenesis.