TargetingPlasmodiumwith constrained peptides and peptidomimetics

Abstract

Malaria remains a worldwide health concern with an estimated quarter of a billion people infected and nearly half a million deaths annually. Malaria is caused by a parasite infection from Plasmodium strains which are transmitted from mosquitoes into the human host. Although several small molecule inhibitors have been found to target the early stages of transmission and prevent parasite proliferation, multiple drug resistant parasite strains have emerged and drug resistance remains a major hurdle. As an alternative to small molecule inhibition, several peptide-based therapeutics have been explored for their potential as antimalarial compounds. Chemically constrained peptides or peptidomimetics were developed to target large binding interfaces of parasite-based proteins that have historically been difficult to selectively inhibit using small molecules. Here, we review ongoing research aimed at developing constrained peptides targeting protein-protein interactions pertinent to malaria pathogenesis. These targets include Falcipain-2, the J domain of CDPK1, myosin A tail domain interacting protein, the PKA signaling pathway, and an unclear signaling pathway involving angiotensin-derived peptides. Diverse synthetic methods were also used for each target. Merging parasite biology with synthetic strategies may provide new opportunities to develop alternative methods for uncovering novel antimalarials and may offer an alternate source for targeting drug-resistant parasite strains.

Allosteric Inhibition of Parkinson’s-Linked LRRK2 by Constrained Peptides

“…Incorporation of the hydrocarbon staple into the desired peptide sequence was done as a strategy to create cell-permeable peptides. The design and synthesis of peptides to effectively disrupt protein–protein interactions has been applied to a diverse array of targets across multiple diseases (for example, see refs − ). Here, we developed constrained peptides designed to target the LRRK2 RocCOR dimerization interface.…”

cAMP-Dependent Signaling Pathways as Potential Targets for Inhibition of Plasmodium falciparum Blood Stages

“…While PPIs may be attractive for inhibitor development, they are often mediated by interfaces that are shallow and elongated, and therefore cannot be easily disrupted using small molecules. Larger, peptide-based inhibitors have been developed to target these surfaces and interactions, and there are several examples developed to target Plasmodium proteins ( Helton and Kennedy, 2020 ). In eukaryotes, a family of A kinase anchoring proteins (AKAPs) interacts with PKA to ensure the correct location for its biological function ( Kennedy and Scott, 2015 ; Bucko and Scott, 2021 ).…”

Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future

“…These motifs can be targeted without affecting the host proteome. A potential obstacle with such peptide-based inhibitors is that they the challenge of bioavailability and membrane permeability must be addressed, as the parasite is localized intracellularly [ 191 , 192 , 193 ]. For drugs to effectively target malaria parasites, they first must cross three membranes: the host RBCs membrane, the parasitophorous vacuole membrane, and the parasite plasma membrane for cytosolic Hsp90.…”