Evolutionary and genetic features of drug targets

Yuan, Quan; Wang, Zhongyi; Chu, Xin-Yi; Zhang, Hongyu

doi:10.1002/med.21487

Cited by 16 publications

(14 citation statements)

References 96 publications

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“…Pathway analysis revealed biological processes enriched for each axonopathy independently, such as glucose metabolism for CMT2 and innate immunity for HSP, as well as for general axonopathies, such as new signaling pathways. Additionally, the identified candidate disease genes may guide exploration into drug target identification 71,75,76 . Sixty of the identified DIAMOnD proteins are present on the updated list of druggable genes: 49 DIAMOnDs may be targeted by a small molecule, 18 DIAMOnDs may be targeted by a biotherapeutic (monoclonal antibody/enzyme or other protein), and 1 DIAMOnD is involved in absorption, distribution, metabolism, and excretion of a compound 76 .…”

Section: Discussionmentioning

confidence: 99%

A network biology approach to unraveling inherited axonopathies

Bis-Brewer

Danzi

Wuchty

et al. 2019

Sci Rep

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Inherited axonopathies represent a spectrum of disorders unified by the common pathological mechanism of length-dependent axonal degeneration. Progressive axonal degeneration can lead to both Charcot-Marie-Tooth type 2 (CMT2) and Hereditary Spastic Paraplegia (HSP) depending on the affected neurons: peripheral motor and sensory nerves or central nervous system axons of the corticospinal tract and dorsal columns, respectively. Inherited axonopathies display an extreme degree of genetic heterogeneity of Mendelian high-penetrance genes. High locus heterogeneity is potentially advantageous to deciphering disease etiology by providing avenues to explore biological pathways in an unbiased fashion. Here, we investigate ‘gene modules’ in inherited axonopathies through a network-based analysis of the Human Integrated Protein-Protein Interaction rEference (HIPPIE) database. We demonstrate that CMT2 and HSP disease proteins are significantly more connected than randomly expected. We define these connected disease proteins as ‘proto-modules’ and show the topological relationship of these proto-modules by evaluating their overlap through a shortest-path based measurement. In particular, we observe that the CMT2 and HSP proto-modules significantly overlapped, demonstrating a shared genetic etiology. Comparison of both modules with other diseases revealed an overlapping relationship between HSP and hereditary ataxia and between CMT2 + HSP and hereditary ataxia. We then use the DIseAse Module Detection (DIAMOnD) algorithm to expand the proto-modules into comprehensive disease modules. Analysis of disease modules thus obtained reveals an enrichment of ribosomal proteins and pathways likely central to inherited axonopathy pathogenesis, including protein processing in the endoplasmic reticulum, spliceosome, and mRNA processing. Furthermore, we determine pathways specific to each axonopathy by analyzing the difference of the axonopathy modules. CMT2-specific pathways include glycolysis and gluconeogenesis-related processes, while HSP-specific pathways include processes involved in viral infection response. Unbiased characterization of inherited axonopathy disease modules will provide novel candidate disease genes, improve interpretation of candidate genes identified through patient data, and guide therapy development.

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Section: Discussionmentioning

confidence: 99%

A network biology approach to unraveling inherited axonopathies

Bis-Brewer

Danzi

Wuchty

et al. 2019

Sci Rep

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“…In addition, there are studies showing that targeting multiple disease genes may have more therapeutic potential [ 11 ], and the genes exert their functions by interaction [ 12 ]. Genetic links between the targets and diseases are critical factors for the treatment effects of combinatorial drugs [ 13 ]. Therefore, we speculated that targeting interacting genes that are disease-related will provide us with information on combinatorial drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies show that targeting multiple disease-associated genes has greater therapeutic potential [ 11 ], and genes often exert functions through molecular interactions [ 12 ]. In addition, the therapeutic potential of chemical agents depends largely on the genetic links between targets and diseases [ 13 ]. The factors that can consolidate these links will enhance an agent’s medicinal potential.…”

Section: Introductionmentioning

confidence: 99%

Facilitating Anti-Cancer Combinatorial Drug Discovery by Targeting Epistatic Disease Genes

Yuan

Liu

et al. 2018

Molecules

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Due to synergistic effects, combinatorial drugs are widely used for treating complex diseases. However, combining drugs and making them synergetic remains a challenge. Genetic disease genes are considered a promising source of drug targets with important implications for navigating the drug space. Most diseases are not caused by a single pathogenic factor, but by multiple disease genes, in particular, interacting disease genes. Thus, it is reasonable to consider that targeting epistatic disease genes may enhance the therapeutic effects of combinatorial drugs. In this study, synthetic lethality gene pairs of tumors, similar to epistatic disease genes, were first targeted by combinatorial drugs, resulting in the enrichment of the combinatorial drugs with cancer treatment, which verified our hypothesis. Then, conventional epistasis detection software was used to identify epistatic disease genes from the genome wide association studies (GWAS) dataset. Furthermore, combinatorial drugs were predicted by targeting these epistatic disease genes, and five combinations were proven to have synergistic anti-cancer effects on MCF-7 cells through cell cytotoxicity assay. Combined with the three-dimensional (3D) genome-based method, the epistatic disease genes were filtered and were more closely related to disease. By targeting the filtered gene pairs, the efficiency of combinatorial drug discovery has been further improved.

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“…Normally, an ideal target contains a series of functional alleles related to the disease phenotypes, which can lead to loss of function (LOF) or gain of function (GOF) of genes, which is caused by certain genetic variants [ 114 , 115 ]. The LOF or GOF of genes may lead to asthma attacks, and the agonists or antagonists that target these genes are potential therapeutic agents [ 6 , 113 ], respectively.…”

Section: Drug Repositioning Based On Geneticsmentioning

confidence: 99%

Genetic Mechanisms of Asthma and the Implications for Drug Repositioning

Huo

Zhang

2018

Genes

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Asthma is a chronic disease that is caused by airway inflammation. The main features of asthma are airway hyperresponsiveness (AHR) and reversible airway obstruction. The disease is mainly managed using drug therapy. The current asthma drug treatments are divided into two categories, namely, anti-inflammatory drugs and bronchodilators. However, disease control in asthma patients is not very efficient because the pathogenesis of asthma is complicated, inducing factors that are varied, such as the differences between individual patients. In this paper, we delineate the genetic mechanisms of asthma, and present asthma-susceptible genes and genetic pharmacology in an attempt to find a diagnosis, early prevention, and treatment methods for asthma. Finally, we reposition some clinical drugs for asthma therapy, based on asthma genetics.

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Evolutionary and genetic features of drug targets

Cited by 16 publications

References 96 publications

A network biology approach to unraveling inherited axonopathies

A network biology approach to unraveling inherited axonopathies

Facilitating Anti-Cancer Combinatorial Drug Discovery by Targeting Epistatic Disease Genes

Genetic Mechanisms of Asthma and the Implications for Drug Repositioning

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