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Application of Multi-Target Phytotherapeutic Concept in Malaria

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Application of Multi-Target Phytotherapeutic Concept in Malaria Tarkang et al. Biomarker Research (2016) 4:25 https://doi.org/10.1186/s40364-016-0077-0 REVIEW Open Access Application of multi-target phytotherapeutic concept in malaria drug discovery: a systems biology approach in biomarker identification Protus Arrey Tarkang1,2*, Regina Appiah-Opong2, Michael F. Ofori3, Lawrence S. Ayong4 and Alexander K. Nyarko2,5 Abstract There is an urgent need for new anti-malaria drugs with broad therapeutic potential and novel mode of action, for effective treatment and to overcome emerging drug resistance. Plant-derived anti-malarials remain a significant source of bioactive molecules in this regard. The multicomponent formulation forms the basis of phytotherapy. Mechanistic reasons for the poly- pharmacological effects of plants constitute increased bioavailability, interference with cellular transport processes, activation of pro-drugs/deactivation of active compounds to inactive metabolites and action of synergistic partners at different points of the same signaling cascade. These effects are known as the multi-target concept. However, due to the intrinsic complexity of natural products-based drug discovery, there is need to rethink the approaches toward understanding their therapeutic effect. This review discusses the multi-target phytotherapeutic concept and its application in biomarker identification using the modified reverse pharmacology - systems biology approach. Considerations include the generation of a product library, high throughput screening (HTS) techniques for efficacy and interaction assessment, High Performance Liquid Chromatography (HPLC)-based anti-malarial profiling and animal pharmacology. This approach is an integrated interdisciplinary implementation of tailored technology platforms coupled to miniaturized biological assays, to track and characterize the multi-target bioactive components of botanicals as well as identify potential biomarkers. While preserving biodiversity, this will serve as a primary step towards the development of standardized phytomedicines, as well as facilitate lead discovery for chemical prioritization and downstream clinical development. Keywords: Malaria, Phytotherapy, Multi-target effects, Reverse pharmacology, High throughput screening (HTS), HPLC-based anti-malarial profiling, In vivo pharmacology, Pharmacokinetics Background in most endemic countries, where there is lack of access Malaria control initiatives have led to substantial im- to modern healthcare facilities and disease monitoring is provement in the number of saved lives in vulnerable not well defined. Most of the populations in these coun- populations, particularly in those with access to effective tries resort to the use of plant-based complementary anti-malarial drugs [1]. In spite of this, Plasmodium fal- medicine for therapy [2]. Drugs derived from natural ciparum malaria remains a major public health burden source, especially herbs, represent a significant propor- tion of the pharmaceutical market, particularly in mal- * Correspondence: [email protected] aria therapy, as well as other infectious diseases. 1 Centre for Research on Medicinal Plants and Traditional Medicine, Institute Examples include quinine from Cinchona species, arte- of Medical Research and Medicinal Plants Studies (IMPM), P. O. Box 8013, Yaoundé, Cameroon misinin from Artemisia annua and atovaquone from 2Department of Clinical Pathology, Noguchi Memorial Institute for Medical Tabebuia impetiginosa [3, 4]. Their advantage for the Research, University of Ghana, P. O. Box LG 581, Legon, Accra, Ghana development of drugs comes from the synergistic Full list of author information is available at the end of the article © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tarkang et al. Biomarker Research (2016) 4:25 Page 2 of 16 interactions of their components and their innate affinity matrices remains the most challenging step due to the for biological receptors [5]. The pharmacological justifi- chemical properties of plant extracts and the mechanism cation of these principles could provide the basis for fur- of their bioactivity [13]. However, the conventional ther development of plant-based traditional medicine as bioactivity-guided isolation involving several iterative a reliable therapeutic tool. steps is first and foremost inefficient and time consum- Malaria parasite has developed resistance to many of ing, especially when the bioactive phytochemical is an the currently available drugs, including emerging resist- unknown compound and exists as a minor component ance to the core artemisinin component of the in the extract. Secondly, if bioactivities of plant extracts artemisinin-based combination (ACT) therapies [6]. This are as a result of the synergistic effects of phytochemi- therefore underscores the need to explore new thera- cals, testing pure phytochemicals in bioassays might not peutic strategies from natural products. Although the be able to fully reveal their bioactivities. Finally, it re- physiopathology of malaria is not fully understood, the quires large amounts of material, thereby destabilizing knowledge that its pathogenesis involves multiple fac- biodiversity. Though successful in the past, this classical tors, obliges effective therapeutic approaches to shift approach relied on several iterative steps which brought from the conventional “one target, one drug” to a new about repeated isolation of the same compounds and it “multi-target, multidrug” model [7, 8]. The requirements could not keep pace with the fast turn around and tight for the development of new anti-malarials to support the deadline of high throughput screening (HTS)-based pro- current therapeutic and eradication agenda include novel grammes [14]. Moreover, in vitro efficacy assays for modes of action with no cross resistance to current these bioactive compounds are usually target-driven and drugs, multiple-stage efficacy and anti-relapsing activity do not allow the detection of truly novel targets or iden- [9]. tification of the complex summary effects due to the in- Herbal medicines are preparations that contain plant teractions of different constituents. This has brought parts (singly or in combination) in a pharmaceutically about renewed interests in holistic in vivo test systems, processed form. Like synthetic drugs, they claim thera- which are more suitable to unravel synergism or identify peutic or prophylactic properties and may exhibit poly- pro-drugs which are converted metabolically to bioactive pharmacological effects through interactions of their substances. To tackle these challenges, new research constituent phytochemicals. Assumed mechanistic rea- strategies employ tools such as metabolomics, a key in sons for these interactions include increased bioavailabil- systems biology, for the diversity-oriented screening of ity, interference with cellular transport processes, herbal medicines. Besides, the normal pharmacological activation of pro-drugs/deactivation of active com- read-outs in malaria infection such as multiple-stage- pounds to inactive metabolites and action of synergistic antiplasmodial, anti-inflammatory, antipyretic, antioxi- partners at different points of the same signaling cas- dant and antinociceptive effects, there is the possibility cade. This concept is known as the multi-target effect of correlating these measurements in a system biological [7]. The application of this concept in drug discovery re- approach with analyzed metabolomics data [15, 16]. quires the comprehensive characterization of the con- Metabolomics, is a key “omics” technology in systems stituent phytochemicals and their bioactivities. biology. It is the comprehensive qualitative and quantita- The multicomponent therapy forms the basis of phy- tive analysis of the bioactive molecules in a cell, organ or totherapy or phytomedicines, where holistic therapeutic organism at a specific point in time. It is a highly versa- effect result from complex positive and negative interac- tile strategy to accelerate deconvolution of active ex- tions between the different components [10]. However, tracts, in which a variety of detection methods are these bioactive components, known as metabolites pos- adopted for metabolite analysis including electrochem- sess high chemo-diversity and constitute the complex ical array, infrared spectroscopy, mass spectrometry biological matrices of these plants. A knowledge of their (MS) and nuclear magnetic resonance (NMR). Amongst pharmacological activities is necessary to understand the the available platforms, the hyphenation of HPLC-MS, basis of their therapeutic effect and this necessitates coupled to NMR spectroscopy is the most widely used broad interdisciplinary research approaches [11, 12]. technology due to its ability to detect and separate a di- Therefore, more than one biological test system is re- verse range of molecules with high sensitivity [17]. quired to measure the therapeutically useful activities, in Summarily, after subjecting chosen
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