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      Drug Design, Development and Therapy (submit here)

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      Potential Impact of the Multi-Target Drug Approach in the Treatment of Some Complex Diseases

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          Abstract

          It is essential to acknowledge the efforts made thus far to manage or eliminate various disease burden faced by humankind. However, the rising global trends of the so-called incurable diseases continue to put pressure on Pharma industries and other drug discovery platforms. In the past, drugs with more than one target were deemed as undesirable options with interest being on the one-drug-single target. Despite the successes of the single-target drugs, it is currently beyond doubt that these drugs have limited efficacy against complex diseases in which the pathogenesis is dependent on a set of biochemical events and several bioreceptors operating concomitantly. Different approaches have thus been proposed to come up with effective drugs to combat even the complex diseases. In the past, the focus was on producing drugs from screening plant compounds; today, we talk about combination therapy and multi-targeting drugs. The multi-target drugs have recently attracted much attention as promising tools to fight against most challenging diseases, and thus a new research focus area. This review will discuss the potential impact of multi-target drug approach on various complex diseases with focus on malaria, tuberculosis (TB), diabetes and neurodegenerative diseases as the main representatives of multifactorial diseases. We will also discuss alternative ideas to solve the current problems bearing in mind the fourth industrial revolution on drug discovery.

          Most cited references107

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Multi-target-directed ligands to combat neurodegenerative diseases.

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              Molecular mechanisms of neurodegeneration in Alzheimer's disease.

              Alzheimer's disease (AD) is characterized by cognitive impairment, progressive neurodegeneration and formation of amyloid-beta (Abeta)-containing plaques and neurofibrillary tangles composed of hyperphosphorylated tau. The neurodegenerative process in AD is initially characterized by synaptic damage accompanied by neuronal loss. In addition, recent evidence suggests that alterations in adult neurogenesis in the hippocampus might play a role. Synaptic loss is one of the strongest correlates to the cognitive impairment in patients with AD. Several lines of investigation support the notion that the synaptic pathology and defective neurogenesis in AD are related to progressive accumulation of Abeta oligomers rather than fibrils. Abnormal accumulation of Abeta resulting in the formation of toxic oligomers is the result of an imbalance between the levels of Abeta production, aggregation and clearance. Abeta oligomers might lead to synaptic damage by forming pore-like structures with channel activity; alterations in glutamate receptors; circuitry hyper-excitability; mitochondrial dysfunction; lysosomal failure and alterations in signaling pathways related to synaptic plasticity, neuronal cell and neurogenesis. A number of signaling proteins, including fyn kinase; glycogen synthase kinase-3beta (GSK3beta) and cyclin-dependent kinase-5 (CDK5), are involved in the neurodegenerative progression of AD. Therapies for AD might require the development of anti-aggregation compounds, pro-clearance pathways and blockers of hyperactive signaling pathways.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                11 August 2020
                2020
                : 14
                : 3235-3249
                Affiliations
                [1 ]Department of Biochemistry, Genetics and Microbiology, Division of Biochemistry, University of Pretoria , Hatfield, South Africa
                [2 ]Laboratory of Research in Medicinal Chemistry (PeQuiM), Institute of Chemistry, Federal University of Alfenas , Alfenas, MG, Brazil
                [3 ]Discipline of Biochemistry, School of Life Sciences, University of KwaZulu-Natal , Durban, South Africa
                Author notes
                Correspondence: Xolani H MakhobaDepartment of Biochemistry, Genetics and Microbiology, Division of Biochemistry, University of Pretoria , Hatfield2000, South AfricaTel +2712 4204149 Email zolanimakhoba53@gmail.com
                Ofentse J PooeDiscipline of Biochemistry, School of Life Sciences, University of KwaZulu-Natal , Private Bag X54001, Durban4000, South AfricaTel +2731 2607664 Email PooeO@ukzn.ac.za
                Author information
                http://orcid.org/0000-0002-7799-992X
                http://orcid.org/0000-0002-7189-2822
                http://orcid.org/0000-0002-8519-2851
                http://orcid.org/0000-0002-2967-7846
                Article
                257494
                10.2147/DDDT.S257494
                7440888
                32884235
                eaca9576-2aa6-4931-b8ff-0848373c6ba6
                © 2020 Makhoba et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 09 April 2020
                : 08 July 2020
                Page count
                Figures: 5, Tables: 3, References: 125, Pages: 15
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                multi-target drugs,malaria,diabetes,tuberculosis and drug discovery

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