Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics

Hopkins, Christopher E.; Brock, Trisha; Caulfield, Thomas R.; Bainbridge, Matthew N.

doi:10.1016/j.mam.2022.101153

Cited by 13 publications

(7 citation statements)

References 137 publications

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“…Drug discovery is usually begins with either in vitro target-engagement screens or phenotypic screens (Zheng et al, 2013). Phenotypic screens have strong advantages over in vitro target-engagement screens, because toxicity and multi-target issues are usually solved simultaneously in the engagement screen (Hopkins et al, 2023). Medicinal plants contain abundant compounds, which can interact with different molecular targets of a disease.…”

Section: Discussionmentioning

confidence: 99%

In vivo antibacterial activity of medicinal plant Sophora flavescens against Streptococcus agalactiae infection

Zhang

Yang²,

et al. 2023

Journal of Fish Diseases

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Streptococcosis disease caused by Streptococcus agalactiae (Group B Streptococcus, GBS) results in a huge economic loss of tilapia culture. It is urgent to find new antimicrobial agents against streptococcosis. In this study, 20 medicinal plants were evaluated in vitro and in vivo to obtain medicinal plants and potential bioactive compounds against GBS infection. The results showed that the ethanol extracts of 20 medicinal plants had low or no antibacterial properties in vitro, with a minimal inhibitory concentration ≥256 mg/L. Interestingly, in vivo tests showed that 7 medicinal plants could significantly inhibit GBS infection in tilapia, and Sophora flavescens (SF) had the strongest anti‐GBS activity in tilapia, reaching 92.68%. SF could significantly reduce the bacterial loads of GBS in different tissues (liver, spleen and brain) of tilapia after treated with different tested concentrations (12.5, 25.0, 50.0 and 100.0 mg/kg) for 24 h. Moreover, 50 mg/kg SF could significantly improve the survival rate of GBS‐infected tilapia by inhibiting GBS replication. Furthermore, the expression of antioxidant gene cat, immune‐related gene c‐type lysozyme and anti‐inflammatory cytokine il‐10 in liver tissue of GBS‐infected tilapia significantly increased after treated with SF for 24 h. Meanwhile, SF significantly reduced the expression of immune‐related gene myd88 and pro‐inflammatory cytokines il‐8 and il‐1β in liver tissue of GBS‐infected tilapia. The negative and positive models of UPLC‐QE‐MS, respectively, identified 27 and 57 components of SF. The major components of SF extract in the negative model were α, α‐trehalose, DL‐malic acid, D‐ (−)‐fructose and xanthohumol, while in the positive model were oxymatrine, formononetin, (−)‐maackiain and xanthohumol. Interestingly, oxymatrine and xanthohumol could significantly inhibit GBS infection in tilapia. Taken together, these results suggest that SF can inhibit GBS infection in tilapia, and it has potential for the development of anti‐GBS agents.

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Section: Discussionmentioning

confidence: 99%

In vivo antibacterial activity of medicinal plant Sophora flavescens against Streptococcus agalactiae infection

Zhang

Yang²,

et al. 2023

Journal of Fish Diseases

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“…C. elegans has emerged as a very efficient small animal model for drug discovery, including in the field of genetic diseases 15,31,32 . Low‐cost maintenance, a fast life cycle, and simplicity of drug/dsRNA delivery make C. elegans an attractive tool for large scale drug tests/screenings 15,16,33 .…”

Section: Discussionmentioning

confidence: 99%

“…elegans has emerged as a very efficient small animal model for drug discovery, including in the field of genetic diseases. 15,31,32 Lowcost maintenance, a fast life cycle, and simplicity of drug/dsRNA delivery make C. elegans an attractive tool for large scale drug tests/screenings. 15,16,33 This offers a very valuable alternative to vertebrate animals whose use in biomedical research is expected to be more and more limited due to stringent bioethical regulations.…”

Section: Discussionmentioning

confidence: 99%

A new Caenorhabditis elegans model to study copper toxicity in Wilson disease

Catalano,

O'Brien,

Mekhova

et al. 2023

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Wilson disease (WD) is caused by mutations in the ATP7B gene that encodes a copper (Cu) transporting ATPase whose trafficking from the Golgi to endo‐lysosomal compartments drives sequestration of excess Cu and its further excretion from hepatocytes into the bile. Loss of ATP7B function leads to toxic Cu overload in the liver and subsequently in the brain, causing fatal hepatic and neurological abnormalities. The limitations of existing WD therapies call for the development of new therapeutic approaches, which require an amenable animal model system for screening and validation of drugs and molecular targets. To achieve this objective, we generated a mutant Caenorhabditis elegans strain with a substitution of a conserved histidine (H828Q) in the ATP7B ortholog cua‐1 corresponding to the most common ATP7B variant (H1069Q) that causes WD. cua‐1 mutant animals exhibited very poor resistance to Cu compared to the wild‐type strain. This manifested in a strong delay in larval development, a shorter lifespan, impaired motility, oxidative stress pathway activation, and mitochondrial damage. In addition, morphological analysis revealed several neuronal abnormalities in cua‐1 mutant animals exposed to Cu. Further investigation suggested that mutant CUA‐1 is retained and degraded in the endoplasmic reticulum, similarly to human ATP7B‐H1069Q. As a consequence, the mutant protein does not allow animals to counteract Cu toxicity. Notably, pharmacological correctors of ATP7B‐H1069Q reduced Cu toxicity in cua‐1 mutants indicating that similar pathogenic molecular pathways might be activated by the H/Q substitution and, therefore, targeted for rescue of ATP7B/CUA‐1 function. Taken together, our findings suggest that the newly generated cua‐1 mutant strain represents an excellent model for Cu toxicity studies in WD.

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“…Drugs targeting CK/CKR may not always be effective due to the presence of genetic variance in population, which need to be addressed by precision personalized medicine (PPM) [25]. Naturally occurring mutations of various CK/CKR have been identified in patients [26] as missense Single nucleotide polymorphisms (SNPs).…”

Section: Introductionmentioning

confidence: 99%

CytoSIP: An annotated structural atlas for interactions involving cytokine or cytokine receptor

Wang

Sun

et al. 2023

Preprint

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Therapeutic agents targeting cytokine-cytokine receptor (CK-CKR) interactions lead to the disruption in cellular signaling and are effective in treating many diseases including tumors. However, a lack of universal and quick access to annotated structural surface regions on CK/CKR has limited the progress of a structure-driven approach in developing targeted macromolecular drugs and precision medicine therapeutics. Herein we report CytoSIP (Single nucleotide polymorphisms (SNPs), Interface, and Phenotype), a database-driven internet application based on atomic interactions around hotspots in experimentally determined CK/CKR structural complexes. CytoSIP contains: (1) SNPs on CK/CKR; (2) interactions involving CK/CKR domains, including CK/CKR interfaces, oligomeric interfaces, epitopes, or other drug-targeting surfaces; and (3) diseases and phenotypes associated with CK/CKR or SNPs. The database framework introduces a unique tri-level SIP data model to bridge genetic variants (atomic level) to disease phenotypes (organism level) using protein structure (complexes) as an underlying framework (molecule level). Customized screening tools are implemented to retrieve relevant CK/CKR subset, which reduces the time and resources needed to interrogate large datasets involving CK/CKR surface hotspots and associated pathologies. CytoSIP portal is publicly accessible (https://CytoSIP.biocloud.top), facilitating the panoramic investigation of the context-dependent crosstalk between CK/CKR and the development of targeted therapeutic agents.

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Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics

Cited by 13 publications

References 137 publications

In vivo antibacterial activity of medicinal plant Sophora flavescens against Streptococcus agalactiae infection

In vivo antibacterial activity of medicinal plant Sophora flavescens against Streptococcus agalactiae infection

A new Caenorhabditis elegans model to study copper toxicity in Wilson disease

CytoSIP: An annotated structural atlas for interactions involving cytokine or cytokine receptor

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