DOCSLIB.ORG

Catestatin, an Endogenous Chromogranin A-Derived Peptide, Inhibits in Vitro Growth of Plasmodium Falciparum

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Catestatin, an Endogenous Chromogranin A-Derived Peptide, Inhibits in Vitro Growth of Plasmodium Falciparum Cell. Mol. Life Sci. (2010) 67:1005–1015 DOI 10.1007/s00018-009-0235-8 Cellular and Molecular Life Sciences RESEARCH ARTICLE Catestatin, an endogenous Chromogranin A-derived peptide, inhibits in vitro growth of Plasmodium falciparum Aziza Akaddar • Ce´cile Doderer-Lang • Melissa R. Marzahn • Franc¸ois Delalande • Marc Mousli • Karen Helle • Alain Van Dorsselaer • Dominique Aunis • Ben M. Dunn • Marie-He´le`ne Metz-Boutigue • Ermanno Candolfi Received: 18 September 2009 / Revised: 3 December 2009 / Accepted: 11 December 2009 / Published online: 31 December 2009 Ó The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Catestatin, an endogenous peptide derived from P. falciparum 3D7, exhibiting 88% inhibition at 20 lM. bovine chromogranin A, and its active domain cateslytin A similar partial inhibition of parasite growth was observed display powerful antimicrobial activities. We have tested for the chloroquine-resistant strain, 7G8 (64%,) and the the activities of catestatin and other related peptides on the multidrug-resistant strain, W2 (62%). In the presence of growth of Plasmodium falciparum in vitro. Catestatin parasite-specific lactate dehydrogenase, a specific protein– inhibits growth of the chloroquine-sensitive strain of protein interaction between catestatin and plasmepsin II precursor was demonstrated. In addition, catestatin par- tially inhibited the parasite-specific proteases plasmepsin in M.-H. Metz-Boutigue and E. Candolfi contributed equally to this vitro. A specific interaction between catestatin and work. plasmepsins II and IV from P. falciparum and plasmepsin Electronic supplementary material The online version of this IV from the three remaining species of Plasmodium known article (doi:10.1007/s00018-009-0235-8) contains supplementary to infect man was observed, suggesting a catestatin- material, which is available to authorized users. induced reduction in availability of nutrients for protein A. Akaddar Á C. Doderer-Lang Á M. Mousli Á E. Candolfi (&) synthesis in the parasite. Institut de Parasitologie et de Pathologie Tropicale, Universite´ de Strasbourg, EA 4438, 67000 Strasbourg, France Keywords Plasmodium falciparum Á e-mail: candolfi@unistra.fr Antimicrobial peptide Á Catestatin Á Cateslytin Á M. R. Marzahn Á B. M. Dunn Chromogranin A Á Plasmepsins II and IV Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, 100245 Gainesville, FL, USA Introduction F. Delalande De´veloppement et Physiopathologie de l’Intestin et du Pancre´as, A series of antimicrobial peptides were derived from the Universite´ de Strasbourg, INSERM U682, processing of the adrenomedullary chromogranins A and B 67200 Strasbourg, France (CgA and CgB), proenkephalin-A, and ubiquitin, all K. Helle co-stored and co-secreted with catecholamines upon stim- Department of Biomedicine, University of Bergen, ulation of the chromaffin cells [1–7]. Eight pairs of dibasic Bergen, Norway residues in bovine CgA correspond to major sites for processing in the intragranular matrix [8] to generate sev- A. Van Dorsselaer Laboratoire de spectrome´trie de masse BioOrganique, eral bioactive peptides [9], among them a 21-residue-long IPHC-DSA, UDS, CNRS, UMR178, 67087 Strasbourg, France cationic peptide (net charge ?5) named catestatin (bovine CgA344–364, bCts). This peptide was initially character- D. Aunis Á M.-H. Metz-Boutigue ized for its inhibitory effect on catecholamine secretion Physiopathologie du Syste`me Nerveux, Universite´ de Strasbourg, INSERM U575, from chromaffin cells of the adrenal medulla [10, 11], and 67084 Strasbourg, France was identified as a product from stimulated chromaffin 1006 A. Akaddar et al. cells [12]. The sequence of Cts is highly conserved in reaction simulations, and microscopic calculations of mammals (Table 1)[13–19], and cateslytin (bovine binding free energies [32]. Malaria parasites, both in cul- CgA344–358, CTL) corresponds to the antimicrobial ture and in animal models, are killed by inhibitors of active domain [2]. The antibacterial potency of the CTL plasmepsins, establishing proof of concept that these pro- domain has been confirmed in studies of Cts as an anti- teases are important as drug targets [33], especially when bacterial agent in human skin [20]. A role for these combined with the inhibition of falcipains that are also antimicrobial CgA peptides in innate immunity was dem- involved in haemoglobin degradation [32]. Previous stud- onstrated by their presence in secretions of stimulated ies have indicated that several peptidomimetics inhibitors, polymorphonuclear neutrophils (PMNs) [2] and by the fact obtained from combinatorial chemistry based peptides that Cts activates neutrophils by inducing calcium entry libraries, have a high inhibitory effect on various plasm- [21]. epsins [34]. Because some of these inhibitors show Malaria is endemic in about 100 developing countries sequence similarities with Cts, we investigated the effect of and over 3 billion people live under the threat of malaria Cts on Plasmodium growth. infection. Malaria causes over 1 million deaths each year, The aim of the present study was to probe Cts and CTL most of whom are children [22, 23]. The most recent for their antimalarial activities. Our results show that Cts estimates indicate that there are more than 500 million inhibits growth of several strains of P. falciparum, not only clinical cases of malaria annually on the planet, a number the chloroquine-sensitive strain 3D7 but also the chloro- that nearly doubles previous estimates [24, 25], and the quine-resistant (7G8) and the multidrug-resistant (W2) disability adjusted life years (DALYs) of malaria are esti- strains. The structural parameters crucial for the antima- mated at 45 million [23]. Furthermore, drug resistance of larial potency have been identified, as well as a potential P. falciparum has emerged in all classes of antimalarial plasmodial target protein within the plasmepsin family [35]. drugs [26, 27], and increased efforts in antimalarial drug discovery are urgently needed [28, 29]. Because some antiplasmodial agents are host cytotoxic molecules [30], Materials and methods natural non-toxic peptides might represent a new approach for malaria drug research. Synthetic peptides Plasmepsins are aspartic proteases involved in the deg- radation of the host cell haemoglobin, providing nutrients The synthetic peptides were prepared with an Applied for parasite growth [31] and other as yet unidentified Biosystems 433 A synthesizer (Foster City, USA), using functions. Novel and potent inhibitors of Plasmodium the stepwise solid-phase method with 9-fluoromethoxy- plasmepsins were identified by using an automated proce- carbonyl (Fmoc chemistry) [2, 36]. As a negative control, dure to post-process the results of a large docking screen of we used the inactive scrambled Cts breaking the putative commercially available compounds. Efforts to design new secondary structure (SLPRRQLPSSAGMRGGKFAYF). inhibitors against malarial plasmepsins have employed a For fluorescence studies, rhodaminated peptides were range of computational tools in the design process, obtained as previously reported [6]. Synthetic peptides including homology modeling, automated docking, enzyme were finally purified by HPLC on C18 reverse-phase Table 1 Alignment of Cts from Sequence Ref. different species and sequence Similarity similarity (%) (%) hCGA352-372 SSMKLSFRARAYGFRGPG P Q L 100 [13] bCGA344-364 RSMRLS FRARGYGFRGPGLQL 90 [14] mCGA364-384 R SMKLSFRTRAYGFRDPGPQL 86 [15] rCGA367-387 R SMKLSFRARAYGFRDPGP Q L 95 [16] eCGA361-381 R SMKLSFRARAYGFRGPGLQL 90 [17] pCGA343-363 RSM KLSFRAPAYGFRGPGLQL 86 [18] Homolog residues are in white letter by comparison with fCGA318-335 RSMKIPT K DQK Y ---EPASEE 38 [19] human Cts h human, b bovine, m mouse, Consensus RSMKL SFRARAYGFR PG QL [13] r rat, e equine, p pig, f frog, sequence R I K G A – deletion Antimalarial activity of Catestatin 1007 columns and lyophylized. Purity of the synthetic peptides experiments, parasitemia was determined by light micro- ([98%) was established by HPLC and MALDI-TOF mass scope (9100), counting the proportion of parasitized red spectrometry, and the concentration was evaluated by blood cells (RBCs) in about 20 fields of thin blood films automatic Edman sequencing [2] after correction with the prepared from culture. Mean and standard deviation were Edman degradation yield. calculated from three different experiments, each being evaluated by three different readers [28]. In parallel, Study of peptide activity on P. falciparum strains Plasmodium-derived lactate dehydrogenase (pLDH), a in vitro parasite-specific intracellular metabolic enzyme, was measured in whole blood in the absence or presence of We have used three P. falciparum strains with different peptides, using a commercial ELISA kit (DiaMed ELISA origin and chemo-sensitivities: an African strain sensitive Malaria Antigen test; Cressier sur Morat, Switzerland) to chloroquine (3D7), a Brazilian strain resistant to chlo- according to the manufacturer’s recommendations [41]. roquine (7G8), and a South-East Asian strain resistant to Each peptide was incubated in MCM at 20 lM for 48 h chloroquine, quinine, and halofantrine (W2), kindly pro- before analysis by pLDH-ELISA. The pLDH test was used vided by Prof. S. Picot (EA 3732 Parasitologie, Mycologie to determine the 50% inhibitory concentration (IC50). The Me´dicale et Pathologie Exotique, Faculte´ de Me´decine, IC50 was estimated by linear regression analysis (standard Universite´
Load more

Recommended publications
  • Membrane Proteins • Cofactors – Plimstex • Membranes • Dna • Small Molecules/Gas • Large Complexes
    Structural mass spectrometry hydrogen/deuterium exchange Petr Man Structural Biology and Cell Signalling Institute of Microbiology, Czech Academy of Sciences Structural biology methods Low-resolution methods High-resolution methods Rigid SAXS IR Raman CD ITC MST Cryo-EM AUC SPR MS X-ray crystallography Chemical cross-linking H/D exchange Native ESI + ion mobility Oxidative labelling Small Large NMR Dynamic Structural biology approaches Simple MS, quantitative MS Cross-linking, top-down, native MS+dissociation native MS+ion mobility Cross-linking Structural MS What can we get using mass spectrometry IM – ion mobility CXL – chemical cross-linking AP – afinity purification OFP – oxidative footprinting HDX – hydrogen/deuterium exchange ISOTOPE EXCHANGE IN PROTEINS 1H 2H 3H occurence [%] 99.988 0.0115 trace 5 …Kaj Ulrik Linderstrøm-Lang „Cartesian diver“ Proteins are migrating in tubes with density gradient until they stop at the point where the densities are equal 1H 2H 3H % 99.9885 0.0115 trace density [g/cm3] 1.000 1.106 1.215 Methods of detection IR: β-: NMR: 1 n = 1.6749 × 10-27 kg MS: 1H 2H 3H výskyt% [%] 99.9885 0.0115 trace hustotadensity vody [g/cm [g/cm3] 3] 1.000 1.106 1.215 jadernýspinspin ½+ 1+ ½+ mass [u] 1.00783 2.01410 3.01605 Factors affecting H/D exchange hydrogen bonding solvent accessibility Factors affecting H/D exchange Side chains (acidity, steric shielding) Bai et al.: Proteins (1993) Glasoe, Long: J. Phys. Chem. (1960) Factors affecting H/D exchange – side chain effects Inductive effect – electron density is Downward shift due to withdrawn from peptide steric hindrance effect of bond (S, O).
    [Show full text]
  • Serine Proteases with Altered Sensitivity to Activity-Modulating
    (19) & (11) EP 2 045 321 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.04.2009 Bulletin 2009/15 C12N 9/00 (2006.01) C12N 15/00 (2006.01) C12Q 1/37 (2006.01) (21) Application number: 09150549.5 (22) Date of filing: 26.05.2006 (84) Designated Contracting States: • Haupts, Ulrich AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 51519 Odenthal (DE) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • Coco, Wayne SK TR 50737 Köln (DE) •Tebbe, Jan (30) Priority: 27.05.2005 EP 05104543 50733 Köln (DE) • Votsmeier, Christian (62) Document number(s) of the earlier application(s) in 50259 Pulheim (DE) accordance with Art. 76 EPC: • Scheidig, Andreas 06763303.2 / 1 883 696 50823 Köln (DE) (71) Applicant: Direvo Biotech AG (74) Representative: von Kreisler Selting Werner 50829 Köln (DE) Patentanwälte P.O. Box 10 22 41 (72) Inventors: 50462 Köln (DE) • Koltermann, André 82057 Icking (DE) Remarks: • Kettling, Ulrich This application was filed on 14-01-2009 as a 81477 München (DE) divisional application to the application mentioned under INID code 62. (54) Serine proteases with altered sensitivity to activity-modulating substances (57) The present invention provides variants of ser- screening of the library in the presence of one or several ine proteases of the S1 class with altered sensitivity to activity-modulating substances, selection of variants with one or more activity-modulating substances. A method altered sensitivity to one or several activity-modulating for the generation of such proteases is disclosed, com- substances and isolation of those polynucleotide se- prising the provision of a protease library encoding poly- quences that encode for the selected variants.
    [Show full text]
  • Protease Inhibition—An Established Strategy to Combat Infectious Diseases
    International Journal of Molecular Sciences Review Protease Inhibition—An Established Strategy to Combat Infectious Diseases Daniel Sojka 1,* , Pavla Šnebergerová 1,2 and Luïse Robbertse 1 1 Biology Centre, Institute of Parasitology, Academy of Sciences of the Czech Republic, Branišovská 1160/31, CZ-37005 Ceskˇ é Budˇejovice,Czech Republic; [email protected] (P.Š.); [email protected] (L.R.) 2 Faculty of Science, University of South Bohemia in Ceskˇ é Budˇejovice,Branišovská 1760c, CZ-37005 Ceskˇ é Budˇejovice,Czech Republic * Correspondence: [email protected] Abstract: Therapeutic agents with novel mechanisms of action are urgently needed to counter the emergence of drug-resistant infections. Several decades of research into proteases of disease agents have revealed enzymes well suited for target-based drug development. Among them are the three recently validated proteolytic targets: proteasomes of the malarial parasite Plasmodium falciparum, aspartyl proteases of P. falciparum (plasmepsins) and the Sars-CoV-2 viral proteases. Despite some unfulfilled expectations over previous decades, the three reviewed targets clearly demonstrate that selective protease inhibitors provide effective therapeutic solutions for the two most impacting infectious diseases nowadays—malaria and COVID-19. Keywords: protease; parasites; inhibition; therapy; infectious diseases Citation: Sojka, D.; Šnebergerová, P.; Robbertse, L. Protease Inhibition—An 1. Introduction Established Strategy to Combat Infectious diseases, along with starvation, limited water resources and the lack of Infectious Diseases. Int. J. Mol. Sci. shelter, are among the main factors threatening the health and prosperity of the world’s 2021, 22, 5762. https://doi.org/ growing human population. Significant proportions of infectious diseases are caused by 10.3390/ijms22115762 parasites [1], the most common human infections being toxoplasmosis, ascariasis, ancy- lostomiasis and trichomoniasis.
    [Show full text]
  • Data-Mining Approaches Reveal Hidden Families of Proteases in The
    Downloaded from genome.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Letter Data-Mining Approaches Reveal Hidden Families of Proteases in the Genome of Malaria Parasite Yimin Wu,1,4 Xiangyun Wang,2 Xia Liu,1 and Yufeng Wang3,5 1Department of Protistology, American Type Culture Collection, Manassas, Virginia 20110, USA; 2EST Informatics, Astrazeneca Pharmaceuticals, Wilmington, Delaware 19810, USA; 3Department of Bioinformatics, American Type Culture Collection, Manassas, Virginia 20110, USA The search for novel antimalarial drug targets is urgent due to the growing resistance of Plasmodium falciparum parasites to available drugs. Proteases are attractive antimalarial targets because of their indispensable roles in parasite infection and development,especially in the processes of host e rythrocyte rupture/invasion and hemoglobin degradation. However,to date,only a small number of protease s have been identified and characterized in Plasmodium species. Using an extensive sequence similarity search,we have identifi ed 92 putative proteases in the P. falciparum genome. A set of putative proteases including calpain,metacaspase,and s ignal peptidase I have been implicated to be central mediators for essential parasitic activity and distantly related to the vertebrate host. Moreover,of the 92,at least 88 have been demonstrate d to code for gene products at the transcriptional levels,based upon the microarray and RT-PCR results,an d the publicly available microarray and proteomics data. The present study represents an initial effort to identify a set of expressed,active,and essential proteases as targets for inhibitor-based drug design. [Supplemental material is available online at www.genome.org.] Malaria remains one of the most dangerous infectious diseases metalloprotease (falcilysin; Eggleson et al.
    [Show full text]
  • Understanding the Structural Basis of Substrate Recognition By
    www.nature.com/scientificreports OPEN Understanding the structural basis of substrate recognition by Plasmodium falciparum plasmepsin V Received: 02 November 2015 Accepted: 20 July 2016 to aid in the design of potent Published: 17 August 2016 inhibitors Rajiv K. Bedi1,*, Chandan Patel2,*, Vandana Mishra1, Huogen Xiao3, Rickey Y. Yada4 & Prasenjit Bhaumik1 Plasmodium falciparum plasmepsin V (PfPMV) is an essential aspartic protease required for parasite survival, thus, considered as a potential drug target. This study reports the first detailed structural analysis and molecular dynamics simulation of PfPMV as an apoenzyme and its complexes with the substrate PEXEL as well as with the inhibitor saquinavir. The presence of pro-peptide in PfPMV may not structurally hinder the formation of a functionally competent catalytic active site. The structure of PfPMV-PEXEL complex shows that the unique positions of Glu179 and Gln222 are responsible for providing the specificity of PEXEL substrate with arginine at P3 position. The structural analysis also reveals that the S4 binding pocket in PfPMV is occupied by Ile94, Ala98, Phe370 and Tyr472, and therefore, does not allow binding of pepstatin, a potent inhibitor of most pepsin-like aspartic proteases. Among the screened inhibitors, the HIV-1 protease inhibitors and KNI compounds have higher binding affinities for PfPMV with saquinavir having the highest value. The presence of a flexible group at P2 and a bulky hydrophobic group at P3 position of the inhibitor is preferred in the PfPMV substrate binding pocket. Results from the present study will aid in the design of potent inhibitors of PMV. Malaria is an infectious disease that is responsible for causing illness in an estimated 200 to 500 million people and results in an annual mortality of 1 to 2 million persons1.
    [Show full text]
  • Nepenthesin from Monkey Cups for Hydrogen/Deuterium Exchange Mass Spectrometry
    University of Calgary PRISM: University of Calgary's Digital Repository Cumming School of Medicine Cumming School of Medicine Research & Publications 2013-02 Nepenthesin from monkey cups for hydrogen/deuterium exchange mass spectrometry. Rey, Martial; Yang, Menglin; Burns, Kyle M.; Yu, Yaping; Lees-Miller, Susan P.; Schriemer, David C. MOLECULAR & CELLULAR PROTEOMICS Rey, M., Yang, M., Burns, K. M., Yu, Y., Lees-Miller, S. P., & Schriemer, D. C. (2013). Nepenthesin from monkey cups for hydrogen/deuterium exchange mass spectrometry. Molecular and Cellular Proteomics, 12(2), 464-472. doi:10.1074/mcp.M112.025221 http://hdl.handle.net/1880/52223 journal article Downloaded from PRISM: https://prism.ucalgary.ca Research © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. This paper is available on line at http://www.mcponline.org Nepenthesin from Monkey Cups for Hydrogen/ Deuterium Exchange Mass Spectrometry*□S Martial Rey‡, Menglin Yang‡, Kyle M. Burns‡, Yaping Yu‡, Susan P. Lees-Miller‡, and David C. Schriemer‡§ Studies of protein dynamics, structure and interactions fication and characterization, but in the last several years it using hydrogen/deuterium exchange mass spectrometry has also become a powerful tool for interrogating protein (HDX-MS) have sharply increased over the past 5–10 structure and dynamics (1, 2). Solution-phase hydrogen/deu- years. The predominant technology requires fast diges- terium exchange (HDX)1, when coupled with mass spectrom- tion at pH 2–3 to retain deuterium label. Pepsin is used etry (MS), provides rich sets of data that can be mined to almost exclusively, but it provides relatively low efficiency extract structural and dynamic parameters from proteins (3– under the constraints of the experiment, and a selectivity 7).
    [Show full text]
  • Handbook of Proteolytic Enzymes Second Edition Volume 1 Aspartic and Metallo Peptidases
    Handbook of Proteolytic Enzymes Second Edition Volume 1 Aspartic and Metallo Peptidases Alan J. Barrett Neil D. Rawlings J. Fred Woessner Editor biographies xxi Contributors xxiii Preface xxxi Introduction ' Abbreviations xxxvii ASPARTIC PEPTIDASES Introduction 1 Aspartic peptidases and their clans 3 2 Catalytic pathway of aspartic peptidases 12 Clan AA Family Al 3 Pepsin A 19 4 Pepsin B 28 5 Chymosin 29 6 Cathepsin E 33 7 Gastricsin 38 8 Cathepsin D 43 9 Napsin A 52 10 Renin 54 11 Mouse submandibular renin 62 12 Memapsin 1 64 13 Memapsin 2 66 14 Plasmepsins 70 15 Plasmepsin II 73 16 Tick heme-binding aspartic proteinase 76 17 Phytepsin 77 18 Nepenthesin 85 19 Saccharopepsin 87 20 Neurosporapepsin 90 21 Acrocylindropepsin 9 1 22 Aspergillopepsin I 92 23 Penicillopepsin 99 24 Endothiapepsin 104 25 Rhizopuspepsin 108 26 Mucorpepsin 11 1 27 Polyporopepsin 113 28 Candidapepsin 115 29 Candiparapsin 120 30 Canditropsin 123 31 Syncephapepsin 125 32 Barrierpepsin 126 33 Yapsin 1 128 34 Yapsin 2 132 35 Yapsin A 133 36 Pregnancy-associated glycoproteins 135 37 Pepsin F 137 38 Rhodotorulapepsin 139 39 Cladosporopepsin 140 40 Pycnoporopepsin 141 Family A2 and others 41 Human immunodeficiency virus 1 retropepsin 144 42 Human immunodeficiency virus 2 retropepsin 154 43 Simian immunodeficiency virus retropepsin 158 44 Equine infectious anemia virus retropepsin 160 45 Rous sarcoma virus retropepsin and avian myeloblastosis virus retropepsin 163 46 Human T-cell leukemia virus type I (HTLV-I) retropepsin 166 47 Bovine leukemia virus retropepsin 169 48
    [Show full text]
  • 1 Peptide Therapeutics
    Universal Free E-Book Store Donate Us, In order to keep our Service Alive, We have to pay for placing files (Abstracts, Books, Literature & Software) on File Hosting Servers, Your donations will make our process of payment a bit easier, Please use any one of the Payment Gateway for Donation. Never matter what amount you donate (10’s or 100’s or 1000’s). Universal Free E-Book Store Universal Free E-Book Store PEPTIDE CHEMISTRY AND DRUG DESIGN Universal Free E-Book Store Universal Free E-Book Store PEPTIDE CHEMISTRY AND DRUG DESIGN Edited by BEN M. DUNN Universal Free E-Book Store Copyright © 2015 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permissions. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose.
    [Show full text]
  • Overexpression of Plasmepsin II and Plasmepsin III Does Not Directly Cause Reduction in Plasmodium Falciparum Sensitivity to Artesunate, Chloroquine T and Piperaquine
    IJP: Drugs and Drug Resistance 9 (2019) 16–22 Contents lists available at ScienceDirect IJP: Drugs and Drug Resistance journal homepage: www.elsevier.com/locate/ijpddr Overexpression of plasmepsin II and plasmepsin III does not directly cause reduction in Plasmodium falciparum sensitivity to artesunate, chloroquine T and piperaquine Duangkamon Loesbanluechaia,b, Namfon Kotanana, Cristina de Cozarc, Theerarat Kochakarna, Megan R. Ansbrod,e, Kesinee Chotivanichf,g, Nicholas J. Whiteg,h, Prapon Wilairati, ∗∗ Marcus C.S. Leee, Francisco Javier Gamoc, Laura Maria Sanzc, Thanat Chookajorna, , ∗ Krittikorn Kümpornsine, a Genomics and Evolutionary Medicine Unit (GEM), Centre of Excellence in Malaria Research, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand b Molecular Medicine Program, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand c Tres Cantos Medicine Development Campus, GlaxoSmithKline, Parque Tecnológico de Madrid, Tres Cantos, 28760, Spain d Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA e Parasites and Microbes Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, United Kingdom f Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand g Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand h Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom i Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand ARTICLE INFO ABSTRACT Keywords: Artemisinin derivatives and their partner drugs in artemisinin combination therapies (ACTs) have played a Artemisinin pivotal role in global malaria mortality reduction during the last two decades.
    [Show full text]
  • A Target Safety Assessment of the Potential Toxicological Risks Of
    Toxicology Research, 2021, 10, 203–213 doi: 10.1093/toxres/tfaa106 Advance Access Publication Date: 15 February 2021 Review REVIEW A target safety assessment of the potential Downloaded from https://academic.oup.com/toxres/article/10/2/203/6135370 by guest on 30 September 2021 toxicological risks of targeting plasmepsin IX/X for the treatment of malaria Jane Barber,1 Phumzile Sikakana,1 Claire Sadler,1 Delphine Baud,2 ∗ Jean-Pierre Valentin3 and Ruth Roberts1,4, 1ApconiX, Alderley Park, Alderley Edge, SK10 4TG, UK, 2Medicines for Malaria Venture, 20 Route de Pré-Bois, Geneva 1215, Switzerland, 3UCB Biopharma SRL, Building R9, Chemin du Foriest, 1420 Braine-l’Alleud, Belgium and 4Biosciences, University of Birmingham, Edgbaston, B15 2TT, UK ∗ Correspondence address. ApconiX, Alderley Park, Alderley Edge, SK10 4DG, UK. Tel: +44 77 33 01 43 96; E-mail: [email protected] Abstract The aspartic proteases plasmepsin IX/X are important antimalarial drug targets due to their specificity to the malaria parasite and their vital role as mediators of disease progression. Focusing on parasite-specific targets where no human homologue exists reduces the possibility of on-target drug toxicity. However, there is a risk of toxicity driven by inadequate selectivity for plasmepsins IX/X in Plasmodium over related mammalian aspartic proteases. Of these, CatD/E may be of most toxicological relevance as CatD is a ubiquitous lysosomal enzyme present in most cell types and CatE is found in the gut and in erythrocytes, the clinically significant site of malarial infection. Based on mammalian aspartic protease physiology and adverse drug reactions (ADRs) to FDA-approved human immunodeficiency virus (HIV) aspartic protease inhibitors, we predicted several potential toxicities including β-cell and congenital abnormalities, hypotension, hypopigmentation, hyperlipidaemia, increased infection risk and respiratory, renal, gastrointestinal, dermatological, and other epithelial tissue toxicities.
    [Show full text]
  • Hemoglobin-Degrading, Aspartic Proteases of Blood-Feeding Parasites SUBSTRATE SPECIFICITY REVEALED by HOMOLOGY MODELS*
    THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 276, No. 42, Issue of October 19, pp. 38844–38851, 2001 © 2001 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. Hemoglobin-degrading, Aspartic Proteases of Blood-feeding Parasites SUBSTRATE SPECIFICITY REVEALED BY HOMOLOGY MODELS* Received for publication, March 2, 2001, and in revised form, August 6, 2001 Published, JBC Papers in Press, August 8, 2001, DOI 10.1074/jbc.M101934200 Ross I. Brinkworth‡, Paul Prociv§, Alex Loukas¶, and Paul J. Brindleyʈ** From the ‡Institute of Molecular Biosciences and §Department of Microbiology and Parasitology, University of Queensland, Brisbane, Queensland 4072, Australia, ¶Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia, and ʈDepartment of Tropical Medicine, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112 Blood-feeding parasites, including schistosomes, hook- and mortality (1). Although phylogenetically unrelated, these worms, and malaria parasites, employ aspartic pro- parasites all share the same food source; they are obligate blood teases to make initial or early cleavages in ingested host feeders, or hematophages. Hb from ingested or parasitized hemoglobin. To better understand the substrate affinity erythrocytes is their major source of exogenous amino acids for Downloaded from of these aspartic proteases, sequences were aligned with growth, development, and reproduction; the Hb, a ϳ64-kDa and/or three-dimensional, molecular models were con- tetrameric polypeptide, is comprehensively catabolized by par- structed of the cathepsin D-like aspartic proteases of asite enzymes to free amino acids or small peptides. Intrigu- schistosomes and hookworms and of plasmepsins of ingly, all these parasites appear to employ cathepsin D-like Plasmodium falciparum and Plasmodium vivax, using aspartic proteases to make initial or early cleavages in the Hb the structure of human cathepsin D bound to the inhib- substrate (2–4).
    [Show full text]
  • Interactions of Ganoderiol-F with Aspartic Proteases of Hiv and Plasmepsin for Anti-Hiv and Anti-Malaria Discovery
    Innovare International Journal of Pharmacy and Pharmaceutical Sciences Academic Sciences ISSN- 0975-1491 Vol 6, Issue 5, 2014 Original Article INTERACTIONS OF GANODERIOL-F WITH ASPARTIC PROTEASES OF HIV AND PLASMEPSIN FOR ANTI-HIV AND ANTI-MALARIA DISCOVERY JUTTI LEVITA *, KEU HENG CHAO, MUTAKIN Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, UniversitasPadjadjaran Jl. Raya Bandung- Sumedang Km 21, Jatinangor, West Java45363, Indonesia. Email: [email protected], [email protected] Received: 07Apr 2014 Revised and Accepted: 12 May 2014 ABSTRACT Objective: HIV-1 has been a killer disease since two decades ago, while a potential cure has not yet discovered due to the fast mutations of the HIV- 1 enzymes,i.e reverse transcriptase, integrase, and protease. Apart of HIV-1, malaria has been the biggest cause of death in human and it is mostly found in the East part of Indonesia. There are some enzymes in the food vacuole of Plasmodium falciparum which are the targets of anti-malaria discovery, e.g. plasmepsin I, II, IV, and histo-aspartic protease (HAP). Both plasmepsin and HIV-1 protease are aspartic proteases, therefore a single drug could be designed to inhibit both enzymes. Ganoderiol-F is a triterpenoid isolated from the stem of Ganodermasinense which shows inhibition on HIV-1 protease with IC 50 20-40 μM. This project was aimed to study and visualize the interaction of ganoderiol-F with HIV-1 protease and plasmepsin I for anti-HIV and anti-malaria discovery. Methods: Preparation of the ligand comprises of geometry optimization using MM+ method and Polak-Ribiere (conjugate gradient) algorithm.
    [Show full text]