Novel drug targets for asthma and COPD: Lessons learned from in vitro and in vivo models

Katie E. Baker; Sara J. Bonvini; Chantal Donovan; Rachel E. Foong; Bing Han; Aruni Jha; Yasin Shaifta; Marieke Smit; Jill R. Johnson; Lyn M. Moir

doi:10.1016/j.pupt.2014.05.008

Sphingosine 1-phosphate in inflammation

Journal of Clinical and Nursing Research ◽

10.26689/jcnr.v4i6.1610 ◽

2020 ◽

Vol 4 (6) ◽

Author(s):

Lijuan Li ◽

Lixia An ◽

Lifang Li ◽

Yongjuan Zhao

Keyword(s):

Plasma Membrane ◽

Drug Targets ◽

Therapeutic Potential ◽

Cell Types ◽

In Vivo Models ◽

Integral Role ◽

Sphingosine 1 Phosphate ◽

And Migration

Sphingolipids are formed via the metabolism of sphingomyelin, aconstituent of the plasma membrane, or by denovosynthesis. Enzymatic pathways result in the formation of several different lipid mediators, which are known to have important roles in many cellular processes, including proliferation, apoptosis and migration. Several studies now suggest that these sphingolipid mediators, including ceramide, ceramide 1-phosphate and sphingosine 1-phosphate (S1P), are likely to have an integral role in in?ammation. This can involve, for example, activation of pro-in?ammatory transcription factors in different cell types and induction of cyclooxygenase-2, leading to production of pro-in?ammatory prostaglandins. The mode of action of each sphingolipid is different. Increased ceramide production leads to the formation of ceramide-rich areas of the membrane, which may assemble signalling complexes, whereas S1P acts via high-af?nity G-protein-coupled S1P receptors on the plasma membrane. Recent studies have demonstrated that in vitro effects of sphingolipids on in?ammation can translate into in vivo models. This review will highlight the areas of research where sphingolipids are involved in in?ammation and the mechanisms of action of each mediator. In addition, the therapeutic potential of drugs that alter sphingolipid actions will be examined with reference to disease states, such as asthma and in?ammatory bowel disease, which involve important in?ammatory components. A signi?cant body of research now indicates that sphingolipids are intimately involved in the in?ammatory process and recent studies have demonstrated that these lipids, together with associated enzymes and receptors, can provide effective drug targets for the treatment of pathological in?ammation.

In Vitro and In Vivo Models to Study the Zoonotic Mosquito-Borne Usutu Virus

Viruses ◽

10.3390/v12101116 ◽

2020 ◽

Vol 12 (10) ◽

pp. 1116

Author(s):

Emna Benzarti ◽

Mutien Garigliany

Keyword(s):

Animal Health ◽

Neurological Complications ◽

Lessons Learned ◽

In Vivo Models ◽

Usutu Virus ◽

The Past ◽

Experimental Systems ◽

Human Infections

Usutu virus (USUV), a mosquito-borne zoonotic flavivirus discovered in South Africa in 1959, has spread to many European countries over the last 20 years. The virus is currently a major concern for animal health due to its expanding host range and the growing number of avian mass mortality events. Although human infections with USUV are often asymptomatic, they are occasionally accompanied by neurological complications reminiscent of those due to West Nile virus (another flavivirus closely related to USUV). Whilst USUV actually appears less threatening than some other emergent arboviruses, the lessons learned from Chikungunya, Dengue, and Zika viruses during the past few years should not be ignored. Further, it would not be surprising if, with time, USUV disperses further eastwards towards Asia and possibly westwards to the Americas, which may result in more pathogenic USUV strains to humans and/or animals. These observations, inviting the scientific community to be more vigilant about the spread and genetic evolution of USUV, have prompted the use of experimental systems to understand USUV pathogenesis and to boost the development of vaccines and antivirals. This review is the first to provide comprehensive coverage of existing in vitro and in vivo models for USUV infection and to discuss their contribution in advancing data concerning this neurotropic virus. We believe that this paper is a helpful tool for scientists to identify gaps in the knowledge about USUV and to design their future experiments to study the virus.

A Review on SARS-CoV-2 Virology, Pathophysiology, Animal Models, and Anti-Viral Interventions

Pathogens ◽

10.3390/pathogens9060426 ◽

2020 ◽

Vol 9 (6) ◽

pp. 426 ◽

Cited By ~ 1

Author(s):

Sabari Nath Neerukonda ◽

Upendra Katneni

Keyword(s):

Clinical Trials ◽

Animal Models ◽

Human Population ◽

Randomized Clinical Trials ◽

Lessons Learned ◽

Highly Pathogenic ◽

In Vivo Models ◽

Antiviral Therapies

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of CoV disease 2019 (COVID-19) is a highly pathogenic and transmissible CoV that is presently plaguing the global human population and economy. No proven effective antiviral therapy or vaccine currently exists, and supportive care remains to be the cornerstone treatment. Through previous lessons learned from SARS-CoV-1 and MERS-CoV studies, scientific groups worldwide have rapidly expanded the knowledge pertaining to SARS-CoV-2 virology that includes in vitro and in vivo models for testing of antiviral therapies and randomized clinical trials. In the present narrative, we review SARS-CoV-2 virology, clinical features, pathophysiology, and animal models with a specific focus on the antiviral and adjunctive therapies currently being tested or that require testing in animal models and randomized clinical trials.

Innovative Methodology in the Discovery of Novel Drug Targets in the Free-Living Amoebae

Current Drug Targets ◽

10.2174/1389450119666180426100452 ◽

2018 ◽

Vol 20 (1) ◽

pp. 60-69 ◽

Cited By ~ 3

Author(s):

Abdul Mannan Baig

Keyword(s):

Drug Targets ◽

Mortality Rates ◽

In Vitro Assays ◽

Cancer Drug ◽

Cns Infection ◽

Free Living ◽

Drug Target Discovery ◽

Novel Drug ◽

Novel Drug Targets

Despite advances in drug discovery and modifications in the chemotherapeutic regimens, human infections caused by free-living amoebae (FLA) have high mortality rates (~95%). The FLA that cause fatal human cerebral infections include Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba spp. Novel drug-target discovery remains the only viable option to tackle these central nervous system (CNS) infection in order to lower the mortality rates caused by the FLA. Of these FLA, N. fowleri causes primary amoebic meningoencephalitis (PAM), while the A. castellanii and B. Mandrillaris are known to cause granulomatous amoebic encephalitis (GAE). The infections caused by the FLA have been treated with drugs like Rifampin, Fluconazole, Amphotericin-B and Miltefosine. Miltefosine is an anti-leishmanial agent and an experimental anti-cancer drug. With only rare incidences of success, these drugs have remained unsuccessful to lower the mortality rates of the cerebral infection caused by FLA. Recently, with the help of bioinformatic computational tools and the discovered genomic data of the FLA, discovery of newer drug targets has become possible. These cellular targets are proteins that are either unique to the FLA or shared between the humans and these unicellular eukaryotes. The latter group of proteins has shown to be targets of some FDA approved drugs prescribed in non-infectious diseases. This review out-lines the bioinformatics methodologies that can be used in the discovery of such novel drug-targets, their chronicle by in-vitro assays done in the past and the translational value of such target discoveries in human diseases caused by FLA.

Aerosol drug delivery to spontaneously-breathing preterm neonates: lessons learned

Respiratory Research ◽

10.1186/s12931-020-01585-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Federico Bianco ◽

Fabrizio Salomone ◽

Ilaria Milesi ◽

Xabier Murgia ◽

Sauro Bonelli ◽

...

Keyword(s):

Lessons Learned ◽

Lung Deposition ◽

Drug Formulation ◽

Preterm Neonates ◽

Extrinsic Factors ◽

In Vivo Models ◽

Factors Affecting ◽

Non Invasive

AbstractDelivery of medications to preterm neonates receiving non-invasive ventilation (NIV) represents one of the most challenging scenarios for aerosol medicine. This challenge is highlighted by the undersized anatomy and the complex (patho)physiological characteristics of the lungs in such infants. Key physiological restraints include low lung volumes, low compliance, and irregular respiratory rates, which significantly reduce lung deposition. Such factors are inherent to premature birth and thus can be regarded to as the intrinsic factors that affect lung deposition. However, there are a number of extrinsic factors that also impact lung deposition: such factors include the choice of aerosol generator and its configuration within the ventilation circuit, the drug formulation, the aerosol particle size distribution, the choice of NIV type, and the patient interface between the delivery system and the patient. Together, these extrinsic factors provide an opportunity to optimize the lung deposition of therapeutic aerosols and, ultimately, the efficacy of the therapy.In this review, we first provide a comprehensive characterization of both the intrinsic and extrinsic factors affecting lung deposition in premature infants, followed by a revision of the clinical attempts to deliver therapeutic aerosols to premature neonates during NIV, which are almost exclusively related to the non-invasive delivery of surfactant aerosols. In this review, we provide clues to the interpretation of existing experimental and clinical data on neonatal aerosol delivery and we also describe a frame of measurable variables and available tools, including in vitro and in vivo models, that should be considered when developing a drug for inhalation in this important but under-served patient population.

Kinomics platform using GBM tissue identifies BTK as being associated with higher patient survival

Life Science Alliance ◽

10.26508/lsa.202101054 ◽

2021 ◽

Vol 4 (12) ◽

pp. e202101054

Author(s):

Sofian Al Shboul ◽

Olimpia E Curran ◽

Javier A Alfaro ◽

Fiona Lickiss ◽

Erisa Nita ◽

...

Keyword(s):

Cell Lines ◽

Drug Targets ◽

Patient Survival ◽

Specific Activity ◽

Ex Vivo ◽

Culture Models ◽

Novel Drug ◽

Btk Inhibitors ◽

Novel Drug Targets

Better understanding of GBM signalling networks in-vivo would help develop more physiologically relevant ex vivo models to support therapeutic discovery. A “functional proteomics” screen was undertaken to measure the specific activity of a set of protein kinases in a two-step cell-free biochemical assay to define dominant kinase activities to identify potentially novel drug targets that may have been overlooked in studies interrogating GBM-derived cell lines. A dominant kinase activity derived from the tumour tissue, but not patient-derived GBM stem-like cell lines, was Bruton tyrosine kinase (BTK). We demonstrate that BTK is expressed in more than one cell type within GBM tissue; SOX2-positive cells, CD163-positive cells, CD68-positive cells, and an unidentified cell population which is SOX2-negative CD163-negative and/or CD68-negative. The data provide a strategy to better mimic GBM tissue ex vivo by reconstituting more physiologically heterogeneous cell co-culture models including BTK-positive/negative cancer and immune cells. These data also have implications for the design and/or interpretation of emerging clinical trials using BTK inhibitors because BTK expression within GBM tissue was linked to longer patient survival.

To Discover the Efficient and Novel Drug Targets in Human Cancers Using CRISPR/Cas Screening and Databases

International Journal of Molecular Sciences ◽

10.3390/ijms222212322 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12322

Author(s):

Iichiroh Onishi ◽

Kouhei Yamamoto ◽

Yuko Kinowaki ◽

Masanobu Kitagawa ◽

Morito Kurata

Keyword(s):

Drug Targets ◽

Gene Editing ◽

Synthetic Lethality ◽

Cancer Therapies ◽

Human Cancers ◽

Genetic Abnormalities ◽

Ideal Tool ◽

Novel Drug ◽

Novel Drug Targets

CRISPR/Cas has emerged as an excelle nt gene-editing technology and is used worldwide for research. The CRISPR library is an ideal tool for identifying essential genes and synthetic lethality targeted for cancer therapies in human cancers. Synthetic lethality is defined as multiple genetic abnormalities that, when present individually, do not affect function or survival, but when present together, are lethal. Recently, many CRISPR libraries are available, and the latest libraries are more accurate and can be applied to few cells. However, it is easier to efficiently search for cancer targets with their own screenings by effectively using databases of CRISPR screenings, such as Depmap portal, PICKLES (Pooled In-Vitro CRISPR Knockout Library Essentiality Screens), iCSDB, Project Score database, and CRISP-view. This review will suggest recent optimal CRISPR libraries and effective databases for Novel Approaches in the Discovery and Design of Targeted Therapies.

Mining the Proteome of Streptococcus mutans for Putative Drug Targets

Infectious Disorders - Drug Targets ◽

10.2174/1871526520666200622143316 ◽

2020 ◽

Vol 20 ◽

Author(s):

Shakti Chandra Vadhana Marimuthu ◽

Haribalaganesh Ravinarayanan ◽

Joseph Christina Rosy ◽

Krishnan Sundar

Keyword(s):

Dental Caries ◽

Streptococcus Mutans ◽

Drug Targets ◽

In Vitro Selection ◽

Target Identification ◽

Dental Enamel ◽

Dental Tissues ◽

Novel Drug ◽

Novel Drug Targets

Background: Dental caries is the most common and one of the prevalent diseases in the world. Streptococcus mutans is one of the major oral pathogen that causes dental caries by forming biofilm on dental tissues, degrading dental enamel and consequent cavitation in the tissue. In vitro selection of drug targets is a laborious and expensive process and therefore computational methods are preferable for target identification at initial stage. Objective: The present research aims to find new drug targets in S. mutans by using subtractive proteomics analysis which implements various bioinformatics tools and databases. Methods: The proteome of S. mutans UA159 was mined for novel drug targets using computational tools and databases such as: CD-HIT, BLASTP, DEG, KAAS and CELL2GO. Results: Out of 1953 proteins of S. mutans UA159, proteins that are non-redundant, non-homologous to human and nonessential to the pathogen were eliminated. Around 178 proteins already available in drug target repositories were also eliminated. Possible functions and subcellular localization of 32 uncharacterized proteins were predicted. Substantially 13 proteins were identified as novel drug targets in S. mutans UA159 that can be targeted by various drugs against dental caries. Conclusion: This study will effectuate the development of novel therapeutic agents against dental carries and other Streptococcal infections.

Drug Leads from Endophytic Fungi: Lessons Learned via Scaled Production

Planta Medica ◽

10.1055/a-1130-4856 ◽

2020 ◽

Vol 86 (13/14) ◽

pp. 988-996 ◽

Cited By ~ 1

Author(s):

Tyler N. Graf ◽

Diana Kao ◽

José Rivera-Chávez ◽

Jacklyn M. Gallagher ◽

Huzefa A. Raja ◽

...

Keyword(s):

Solid Phase ◽

Lessons Learned ◽

In Vivo Studies ◽

Fungal Culture ◽

In Vivo Models ◽

Study Materials ◽

Penicillium Restrictum ◽

Judicious Choice

AbstractRecently, the isolation and elucidation of a series of polyhydroxyanthraquinones were reported from an organic extract of a solid phase culture of an endophytic fungus, Penicillium restrictum (strain G85). One of these compounds, ω-hydroxyemodin (1), showed promising quorum-sensing inhibition against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) in both in vitro and in vivo models. The initial supply of 1 was 19 mg, and this amount needed to be scaled by a factor of 30 to 50 times, in order to generate material for further in vivo studies. To do so, improvements were implemented to enhance both the fermentation of the fungal culture and the isolation of this compound, with the target of generating > 800 mg of study materials in a period of 13 wk. Valuable insights, both regarding chemistry and mycology, were gained during the targeted production of 1 on the laboratory-scale. In addition, methods were modified to make the process more environmentally friendly by judicious choice of solvents, implementing procedures for solvent recycling, and minimizing the use of halogenated solvents.

Cofactor Independent Phosphoglycerate Mutase ofBrugia malayiInduces a Mixed Th1/Th2 Type Immune Response and Inhibits Larval Development in the Host

BioMed Research International ◽

10.1155/2014/590281 ◽

2014 ◽

Vol 2014 ◽

pp. 1-19 ◽

Cited By ~ 7

Author(s):

Prashant K. Singh ◽

Susheela Kushwaha ◽

Ajay K. Rana ◽

Shailja Misra-Bhattacharya

Keyword(s):

Immune Response ◽

Drug Targets ◽

Phosphoglycerate Mutase ◽

Effective Vaccine ◽

Secretory Product ◽

Mastomys Coucha ◽

Novel Drug

Lymphatic filariasis is a major debilitating disease, endemic in 72 countries putting more than 1.39 billion people at risk and 120 million are already infected. Despite the significant progress in chemotherapeutic advancements, there is still need for other measures like development of an effective vaccine or discovery of novel drug targets. In this study, structural and immunological characterization of independent phosphoglycerate mutase of filarial parasiteBrugia malayiwas carried out. Protein was found to be expressed in all major parasite life stages and as an excretory secretory product of adult parasites. Bm-iPGM also reacted to all the categories of human bancroftian patient’s sera including endemic normals.In vivoimmunological behaviour of protein was determined in immunized BALB/c mice followed by prophylactic analysis in BALB/c mice andMastomys coucha. Immunization with Bm-iPGM led to generation of a mixed Th1/Th2 type immune response offering 58.2% protection against larval challenge in BALB/c and 65–68% protection inM. coucha.In vitrostudies confirmed participation of anti-Bm-iPGM antibodies in killing ofB. malayiinfective larvae and microfilariae through ADCC mechanism. The present findings reveal potential immunoprotective nature of Bm-iPGM advocating its worth as an antifilarial vaccine candidate.