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Potential New Drug Targets and Therapeutic Approaches for Parasitic Nematode Infections Melanie Abongwa Iowa State University

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Potential New Drug Targets and Therapeutic Approaches for Parasitic Nematode Infections Melanie Abongwa Iowa State University Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2017 Potential new drug targets and therapeutic approaches for parasitic nematode infections Melanie Abongwa Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Toxicology Commons Recommended Citation Abongwa, Melanie, "Potential new drug targets and therapeutic approaches for parasitic nematode infections" (2017). Graduate Theses and Dissertations. 15240. https://lib.dr.iastate.edu/etd/15240 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Potential new drug targets and therapeutic approaches for parasitic nematode infections by Melanie Abongwa A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Toxicology Program of Study Committee: Richard J. Martin, Co-major Professor Alan P. Robertson, Co-major Professor Michael John Kimber Vellareddy Anantharam Douglas E. Jones The student author and the program of study committee are solely responsible for the content of this dissertation. The Graduate College will ensure this dissertation is globally accessible and will not permit alterations after a degree is conferred. Iowa State University Ames, Iowa 2017 Copyright © Melanie Abongwa, 2017. All rights reserved. ii DEDICATION This dissertation research is dedicated to my loving and caring parents James T. and Comfort A. Abongwa, and my siblings Delphine N. Terence A., and Willibrod A. Abongwa. iii TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ................................................................................................ viii ABSTRACT ........................................................................................................................ xi CHAPTER 1: GENERAL INTRODUCTION ................................................................... 1 1.1 Introduction ............................................................................................................. 1 1.2 Thesis Organization ................................................................................................ 2 CHAPTER 2. LITERATURE REVIEW ............................................................................ 5 2.1 Parasitic Nematodes ................................................................................................ 5 2.1.1 Soil-transmitted helminthiases ....................................................................... 9 2.1.1.1 Ascariasis .............................................................................................. 9 2.1.2 Filariases ........................................................................................................ 12 2.1.2.1 Onchocerciasis (River blindness) ......................................................... 12 2.1.2.2 Lymphatic filariasis (Elephantiasis) ..................................................... 18 2.2 Nematode Neuromuscular System .......................................................................... 22 2.2.1 Nervous System ............................................................................................. 23 2.2.2 Muscular System ............................................................................................ 23 2.3 Nicotinic Acetylcholine Receptors (nAChRs) ........................................................ 24 2.3.1 Caenorhabditis elegans nAChRs ................................................................... 27 2.3.2 Parasitic nematode nAChRs .......................................................................... 34 2.3.3 Vertebrate nAChRs ........................................................................................ 39 2.4 Medicinal plants ...................................................................................................... 41 2.4.1 Daniellia oliveri ............................................................................................. 43 2.4.2 Psorospermum febrifugum ............................................................................. 44 2.4.3 The drug development pipeline ..................................................................... 44 2.5 Anthelmintics and anthelmintic resistance ............................................................. 47 2.5.1 Anthelmintics ................................................................................................. 47 2.5.1.1 Benzimidazoles (BZs) ........................................................................... 48 2.5.1.2 Imidazothiazoles ................................................................................... 49 2.5.1.3 Tetrahydropyrimidines .......................................................................... 50 2.5.1.4 Macrocyclic lactones (MLs) ................................................................. 51 2.5.1.5 Amino-acetonitrile derivatives (AADs) ................................................ 53 2.5.1.6 Spiroindoles .......................................................................................... 54 2.5.1.7 Cyclooctadepsipeptides......................................................................... 55 2.5.1.8 Tribendimidine ...................................................................................... 57 2.5.2 Anthelmintic resistance .................................................................................. 59 2.6 Xenopus laevis oocytes heterologous expression system ....................................... 62 iv CHAPTER 3. PHARMACOLOGICAL PROFILE OF ASCARIS SUUM ACR-16, A NEW HOMOMERIC NICOTINIC ACETYLCHOLINE RECEPTOR WIDELY DISTRIBUTED IN ASCARIS TISSUES ............................................................................ 66 3.1 Summary ................................................................................................................. 66 3.1.1 Background and Purpose ............................................................................... 66 3.1.2 Experimental Approach ................................................................................. 66 3.1.3 Key Results .................................................................................................... 67 3.1.4 Conclusions and Implications ........................................................................ 67 3.2 Abbreviations .......................................................................................................... 67 3.3 Table of Links ......................................................................................................... 68 3.4 Introduction ............................................................................................................. 68 3.5 Methods................................................................................................................... 70 3.5.1 Animals .......................................................................................................... 70 3.5.2 Sequence analysis .......................................................................................... 70 3.5.3 Asu-ACR-16 receptor localization ................................................................. 71 3.5.4 cRNA preparation .......................................................................................... 72 3.5.5 Oocyte microinjection .................................................................................... 73 3.5.6 Two-electrode voltage clamp electrophysiology (TEVC) in Xenopus Oocytes ............................................................................................................. 73 3.5.7 Assessment of agonists and antagonists ........................................................ 74 3.5.8 Permeability of receptors to calcium ............................................................. 75 3.5.9 Data and statistical analysis ........................................................................... 76 3.6 Materials ................................................................................................................. 78 3.7 Results ..................................................................................................................... 78 3.7.1 Identification of Asu-ACR-16 sequence ........................................................ 78 3.7.2 Asu-ACR-16 sequence suggests pharmacological differences to host mammalian α7 nAChRs .................................................................................... 79 3.7.3 Ubiquitous tissue and single-cell expression of ACR-16 in Asu ................... 82 3.7.4 ric-3 is required for functional expression of Asu-ACR-16 ........................... 84 3.7.5 Asu-ACR-16 forms a nicotine-sensitive but levamisole-insensitive nAChR .............................................................................................................. 86 3.7.6 Asu-ACR-16 desensitization .......................................................................... 87 3.7.7 Nicotine as a potent agonist ........................................................................... 89 3.7.8 Rank order antagonist potencies: Asu-ACR-16 is not sensitive to α-BTX .... 90 3.7.9 Non-competitive derquantel antagonism and mixed antagonism of dHβE ... 90
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