Inhibition of heme sequestration of histidine-rich protein 2 using multiple epitope-targeted peptides
Autor: | David N. Bunck, JingXin Liang, James R. Heath, Sunga Hong, Anvita Mishra, Matthew N. Idso |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Biocrystallization
Molecular Conformation Protozoan Proteins Antigens Protozoan Heme 010402 general chemistry 01 natural sciences Biochemistry Epitope chemistry.chemical_compound Epitopes Structural Biology Chloroquine Drug Discovery parasitic diseases medicine Humans Amino Acid Sequence Molecular Biology Peptide sequence Histidine Pharmacology biology 010405 organic chemistry Chemistry Hemozoin Organic Chemistry Plasmodium falciparum General Medicine biology.organism_classification Recombinant Proteins 0104 chemical sciences Molecular Medicine Peptides medicine.drug |
Popis: | Plasmodium falciparum is the most lethal species of malaria. In infected human red blood cells, P. falciparum digests hemoglobin as a nutrient source, liberating cytotoxic free heme in the process. Sequestration and subsequent conversion of this byproduct into hemozoin, an inert biocrystalline heme aggregate, plays a key role in parasite survival. Hemozoin has been a longstanding target of antimalarials such as chloroquine (CQ), which inhibit the biocrystallization of free heme. In this study, we explore heme-binding interactions with histidine-rich-protein 2 (HRP2), a known malarial biomarker and purported player in free heme sequestration. HRP2 is notoriously challenging to target due to its highly repetitious sequence and irregular secondary structure. We started with three protein-catalyzed capture agents (PCCs) developed against epitopes of HRP2, inclusive of heme-binding motifs, and explored their ability to inhibit heme:HRP2 complex formation. Cocktails of the individual PCCs exhibit an inhibitory potency similar to CQ, while a covalently linked structure built from two separate PCCs provided considerably increased inhibition relative to CQ. Epitope-targeted disruption of heme:HRP2 binding is a novel approach towards disrupting P. falciparum-related hemozoin formation. |
Databáze: | OpenAIRE |
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