title: The Stapled AKAP Disruptor Peptide STAD-2 Displays Antimalarial Activity through a PKA-Independent Mechanism.
abstract: Drug resistance poses a significant threat to ongoing malaria control efforts. Coupled with lack of a malaria vaccine, there is an urgent need for the development of new antimalarials with novel mechanisms of action and low susceptibility to parasite drug resistance. Protein Kinase A (PKA) has been implicated as a critical regulator of pathogenesis in malaria. Therefore, we sought to investigate the effects of disrupted PKA signaling as a possible strategy for inhibition of parasite replication. Host PKA activity is partly regulated by a class of proteins called A Kinase Anchoring Proteins (AKAPs), and interaction between HsPKA and AKAP can be inhibited by the stapled peptide Stapled AKAP Disruptor 2 (STAD-2). STAD-2 was tested for permeability to and activity against Plasmodium falciparum blood stage parasites in vitro. The compound was selectively permeable only to infected red blood cells (iRBC) and demonstrated rapid antiplasmodial activity, possibly via iRBC lysis (IC50 ≈ 1 μM). STAD-2 localized within the parasite almost immediately post-treatment but showed no evidence of direct association with PKA, indicating that STAD-2 acts via a PKA-independent mechanism. Furosemide-insensitive parasite permeability pathways in the iRBC were largely responsible for uptake of STAD-2. Further, peptide import was highly specific to STAD-2 as evidenced by low permeability of control stapled peptides. Selective uptake and antiplasmodial activity of STAD-2 provides important groundwork for the development of stapled peptides as potential antimalarials. Such peptides may also offer an alternative strategy for studying protein-protein interactions critical to parasite development and pathogenesis.
authors.affiliation: Department of Infectious Diseases, University of Georgia College of Veterinary Medicine, Athens, Georgia, United States of America; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Briana R
authors.initials: BR
authors.lastname: Flaherty
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Yuxiao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, University of Georgia College of Veterinary Medicine, Athens, Georgia, United States of America.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Trope
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Tienhuei G
authors.initials: TG
authors.lastname: Ho
authors.affiliation: Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, United States of America; Department of Cellular Biology, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Vasant
authors.initials: V
authors.lastname: Muralidharan
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Eileen J
authors.initials: EJ
authors.lastname: Kennedy
authors.affiliation: Department of Infectious Diseases, University of Georgia College of Veterinary Medicine, Athens, Georgia, United States of America; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, United States of America.
authors.forename: David S
authors.initials: DS
authors.lastname: Peterson
mesh_terms: D054758:A Kinase Anchor Proteins / Q000737:chemistry / Q000378:metabolism; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D015800:Protozoan Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D054758:A Kinase Anchor Proteins; D000962:Antimalarials; D010455:Peptides; D015800:Protozoan Proteins; D017868:Cyclic AMP-Dependent Protein Kinases