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Inhibition of heme sequestration of histidine-rich protein 2 using multiple epitope-targeted peptides

Liang, JingXin and Bunck, David N. and Mishra, Anvita and Hong, Sunga and Idso, Matthew N. and Heath, James R. (2019) Inhibition of heme sequestration of histidine-rich protein 2 using multiple epitope-targeted peptides. Journal of Peptide Science, 25 (9). Art. No. e3203. ISSN 1075-2617. http://resolver.caltech.edu/CaltechAUTHORS:20190729-100027029

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/psc.3203DOIArticle
ORCID:
AuthorORCID
Liang, JingXin0000-0001-6600-8409
Heath, James R.0000-0001-5356-4385
Additional Information:© 2019 European Peptide Society and John Wiley & Sons, Ltd. Version of Record online: 25 July 2019; Manuscript accepted: 19 June 2019; Manuscript revised: 18 June 2019; Manuscript received: 16 April 2019. Funding Information: Jean Perkins Foundation; Institute for Collaborative Biotechnologies. Grant Number: W911NF‐09‐D‐0001; Bill and Melinda Gates Foundation
Funders:
Funding AgencyGrant Number
Jean Perkins FoundationUNSPECIFIED
Army Research Office (ARO)W911NF‐09‐D‐0001
Bill and Melinda Gates FoundationUNSPECIFIED
Issue or Number:9
Record Number:CaltechAUTHORS:20190729-100027029
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20190729-100027029
Official Citation: Liang, JX, Bunck, DN, Mishra, A, Hong, S, Idso, MN, Heath, JR. Inhibition of heme sequestration of histidine‐rich protein 2 using multiple epitope‐targeted peptides. J Pep Sci. 2019; 25:e3203. https://doi.org/10.1002/psc.3203
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:97482
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:29 Jul 2019 17:07
Last Modified:03 Sep 2019 16:06

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