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Article ; Online: Galanin receptor 3 - A new pharmacological target in retina degeneration.

Ortega, Joseph T / Parmar, Tanu / Jastrzebska, Beata

2023 Volume 188, Page(s) 106675

Abstract: The neuropeptide galanin receptor 3 (GALR3) is a class A G protein-coupled receptor (GPCR) broadly expressed in the nervous system, including the retina. GALR3 is involved in the modulation of immune and inflammatory responses. Tight control of these ... ...

Abstract	The neuropeptide galanin receptor 3 (GALR3) is a class A G protein-coupled receptor (GPCR) broadly expressed in the nervous system, including the retina. GALR3 is involved in the modulation of immune and inflammatory responses. Tight control of these processes is critical for maintaining homeostasis in the retina and is required to sustain vision. Here, we investigated the role of GALR3 in retina pathologies triggered by bright light and P23H mutation in the rhodopsin (RHO) gene, associated with the activation of oxidative stress and inflammatory responses. We used a multiphase approach involving pharmacological inhibition of GALR3 with its antagonist SNAP-37889 and genetic depletion of GALR3 to modulate the GALR3 signaling. Our in vitro experiments in the retinal pigment epithelium-derived cells (ARPE19) susceptible to all-trans-retinal toxicity indicated that GALR3 could be involved in the cellular stress response to this phototoxic product. Indeed, blocking the GALR3 signaling in Abca4
MeSH term(s)	Mice ; Animals ; Retinal Degeneration/drug therapy ; Retinal Degeneration/genetics ; Receptor, Galanin, Type 3/genetics ; Retinitis Pigmentosa/genetics ; Retinitis Pigmentosa/pathology ; Retina/pathology ; Mutation ; Disease Models, Animal ; ATP-Binding Cassette Transporters/genetics
Chemical Substances	Receptor, Galanin, Type 3 ; Abca4 protein, mouse ; ATP-Binding Cassette Transporters
Language	English
Publishing date	2023-01-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2023.106675
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Article: Rhodopsin as a Molecular Target to Mitigate Retinitis Pigmentosa.

Ortega, Joseph T / Jastrzebska, Beata

Advances in experimental medicine and biology

2021 Volume 1371, Page(s) 61–77

Abstract: Retinitis pigmentosa (RP) is a group of hereditary degenerative diseases affecting 1 of 4000 people worldwide and being the most prevalent cause of visual handicap among working populations in developed countries. These disorders are mainly related to ... ...

Abstract	Retinitis pigmentosa (RP) is a group of hereditary degenerative diseases affecting 1 of 4000 people worldwide and being the most prevalent cause of visual handicap among working populations in developed countries. These disorders are mainly related to the abnormalities in the rod G protein-coupled receptor (GPCR), rhodopsin reflected in the dysregulated membrane trafficking, stability and phototransduction processes that lead to progressive loss of retina function and eventually blindness. Currently, there is no cure for RP, and the therapeutic options are limited. Targeting rhodopsin with small molecule chaperones to improve the folding and stability of the mutant receptor is one of the most promising pharmacological approaches to alleviate the pathology of RP. This review provides an update on the current knowledge regarding small molecule compounds that have been evaluated as rhodopsin modulators to be considered as leads for the development of novel therapies for RP.
MeSH term(s)	Carrier Proteins ; Humans ; Molecular Chaperones ; Mutation ; Receptors, G-Protein-Coupled/genetics ; Retinitis Pigmentosa/drug therapy ; Retinitis Pigmentosa/genetics ; Retinitis Pigmentosa/pathology ; Rhodopsin/genetics ; Rhodopsin/metabolism
Chemical Substances	Carrier Proteins ; Molecular Chaperones ; Receptors, G-Protein-Coupled ; Rhodopsin (9009-81-8)
Language	English
Publishing date	2021-12-28
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/5584_2021_682
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Article ; Online: The Retinoid and Non-Retinoid Ligands of the Rod Visual G Protein-Coupled Receptor.

Ortega, Joseph T / Jastrzebska, Beata

International journal of molecular sciences

2019 Volume 20, Issue 24

Abstract: G protein-coupled receptors (GPCRs) play a predominant role in the drug discovery effort. These cell surface receptors are activated by a variety of specific ligands that bind to the orthosteric binding pocket located in the extracellular part of the ... ...

Abstract	G protein-coupled receptors (GPCRs) play a predominant role in the drug discovery effort. These cell surface receptors are activated by a variety of specific ligands that bind to the orthosteric binding pocket located in the extracellular part of the receptor. In addition, the potential binding sites located on the surface of the receptor enable their allosteric modulation with critical consequences for their function and pharmacology. For decades, drug discovery focused on targeting the GPCR orthosteric binding sites. However, finding that GPCRs can be modulated allosterically opened a new venue for developing novel pharmacological modulators with higher specificity. Alternatively, focus on discovering of non-retinoid small molecules beneficial in retinopathies associated with mutations in rhodopsin is currently a fast-growing pharmacological field. In this review, we summarize the accumulated knowledge on retinoid ligands and non-retinoid modulators of the light-sensing GPCR, rhodopsin and their potential in combating the specific vision-related pathologies. Also, recent findings reporting the potential of biologically active compounds derived from natural products as potent rod opsin modulators with beneficial effects against degenerative diseases related to this receptor are highlighted here.
MeSH term(s)	Allosteric Regulation/drug effects ; Animals ; Binding Sites ; Drug Discovery ; Humans ; Ligands ; Models, Molecular ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/drug effects ; Receptors, G-Protein-Coupled/metabolism ; Small Molecule Libraries/pharmacology
Chemical Substances	Ligands ; Receptors, G-Protein-Coupled ; Small Molecule Libraries
Language	English
Publishing date	2019-12-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20246218
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Article ; Online: Retinoid analogs and polyphenols as potential therapeutics for age-related macular degeneration.

Parmar, Tanu / Ortega, Joseph T / Jastrzebska, Beata

Experimental biology and medicine (Maywood, N.J.)

2020 Volume 245, Issue 17, Page(s) 1615–1625

Abstract: Impact statement: Age-related macular degeneration (AMD) is a devastating retinal degenerative disease. Epidemiological reports showed an expected increasing prevalence of AMD in the near future. The only one existing FDA-approved pharmacological ... ...

Abstract	Impact statement: Age-related macular degeneration (AMD) is a devastating retinal degenerative disease. Epidemiological reports showed an expected increasing prevalence of AMD in the near future. The only one existing FDA-approved pharmacological treatment involves an anti-vascular endothelial growth factor (VEGF) therapy with serious disadvantages. This limitation emphasizes an alarming need to develop new therapeutic approaches to prevent and treat AMD. In this review, we summarize scientific data unraveling the therapeutic potential of the specific retinoid and natural compounds. The experimental results reported by us and other research groups demonstrated that retinoid analogs and compounds with natural product scaffolds could serve as lead compounds for the development of new therapeutic agents with potential to prevent or slow down the pathogenesis of AMD.
MeSH term(s)	Animals ; Biological Products/therapeutic use ; Humans ; Macular Degeneration/drug therapy ; Macular Degeneration/prevention & control ; Polyphenols/chemistry ; Polyphenols/therapeutic use ; Retinal Pigments/metabolism ; Retinoids/chemistry ; Retinoids/therapeutic use ; Risk Factors
Chemical Substances	Biological Products ; Polyphenols ; Retinal Pigments ; Retinoids
Language	English
Publishing date	2020-05-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	4015-0
ISSN	1535-3699 ; 1525-1373 ; 0037-9727
ISSN (online)	1535-3699 ; 1525-1373
ISSN	0037-9727
DOI	10.1177/1535370220926938
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Article ; Online: Correlating electrochemical stimulus to structural change in liquid electron microscopy videos using the structural dissimilarity metric.

Mulvey, Justin T / Iyer, Katen P / Ortega, Tomàs / Merham, Jovany G / Pivak, Yevheniy / Sun, Hongyu / Hochbaum, Allon I / Patterson, Joseph P

Ultramicroscopy

2023 Volume 257, Page(s) 113894

Abstract: In-situ liquid cell transmission electron microscopy (LCTEM) with electrical biasing capabilities has emerged as an invaluable tool for directly imaging electrode processes with high temporal and spatial resolution. However, accurately quantifying ... ...

Abstract	In-situ liquid cell transmission electron microscopy (LCTEM) with electrical biasing capabilities has emerged as an invaluable tool for directly imaging electrode processes with high temporal and spatial resolution. However, accurately quantifying structural changes that occur on the electrode and subsequently correlating them to the applied stimulus remains challenging. Here, we present structural dissimilarity (DSSIM) analysis as segmentation-free video processing algorithm for locally detecting and quantifying structural change occurring in LCTEM videos. In this study, DSSIM analysis is applied to two in-situ LCTEM videos to demonstrate how to implement this algorithm and interpret the results. We show DSSIM analysis can be used as a visualization tool for qualitative data analysis by highlighting structural changes which are easily missed when viewing the raw data. Furthermore, we demonstrate how DSSIM analysis can serve as a quantitative metric and efficiently convert 3-dimensional microscopy videos to 1-dimenional plots which makes it easy to interpret and compare events occurring at different timepoints in a video. In the analyses presented here, DSSIM is used to directly correlate the magnitude and temporal scale of structural change to the features of the applied electrical bias. ImageJ, Python, and MATLAB programs, including a user-friendly interface and accompanying documentation, are published alongside this manuscript to make DSSIM analysis easily accessible to the scientific community.
Language	English
Publishing date	2023-11-24
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1479043-9
ISSN	1879-2723 ; 0304-3991
ISSN (online)	1879-2723
ISSN	0304-3991
DOI	10.1016/j.ultramic.2023.113894
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Article ; Online: Structural basis for DNA targeting by the Tn7 transposon.

Shen, Yao / Gomez-Blanco, Josue / Petassi, Michael T / Peters, Joseph E / Ortega, Joaquin / Guarné, Alba

Nature structural & molecular biology

2022 Volume 29, Issue 2, Page(s) 143–151

Abstract: Tn7 transposable elements are unique for their highly specific, and sometimes programmable, target-site selection mechanisms and precise insertions. All the elements in the Tn7 family utilize an AAA+ adaptor (TnsC) to coordinate target-site selection ... ...

Abstract	Tn7 transposable elements are unique for their highly specific, and sometimes programmable, target-site selection mechanisms and precise insertions. All the elements in the Tn7 family utilize an AAA+ adaptor (TnsC) to coordinate target-site selection with transpososome assembly and to prevent insertions at sites already containing a Tn7 element. Owing to its multiple functions, TnsC is considered the linchpin in the Tn7 element. Here we present the high-resolution cryo-EM structure of TnsC bound to DNA using a gain-of-function variant of the protein and a DNA substrate that together recapitulate the recruitment to a specific DNA target site. TnsC forms an asymmetric ring on target DNA that segregates target-site selection and interaction with the paired-end complex to opposite faces of the ring. Unlike most AAA+ ATPases, TnsC uses a DNA distortion to find the target site but does not remodel DNA to activate transposition. By recognizing pre-distorted substrates, TnsC creates a built-in regulatory mechanism where ATP hydrolysis abolishes ring formation proximal to an existing element. This work unveils how Tn7 and Tn7-like elements determine the strict spacing between the target and integration sites.
MeSH term(s)	Binding Sites/genetics ; Crystallography, X-Ray ; DNA Transposable Elements/genetics ; DNA, Bacterial/chemistry ; DNA, Bacterial/genetics ; DNA, Bacterial/metabolism ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Escherichia coli Proteins/chemistry ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; Models, Molecular ; Protein Interaction Domains and Motifs ; Protein Structure, Quaternary ; Substrate Specificity ; Transposases/chemistry ; Transposases/genetics ; Transposases/metabolism
Chemical Substances	DNA Transposable Elements ; DNA, Bacterial ; DNA-Binding Proteins ; Escherichia coli Proteins ; TnsC protein, E coli ; Transposases (EC 2.7.7.-)
Language	English
Publishing date	2022-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/s41594-022-00724-8
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Article ; Online: Class A G Protein-Coupled Receptor Antagonist Famotidine as a Therapeutic Alternative Against SARS-CoV2: An In Silico Analysis.

Ortega, Joseph T / Serrano, Maria Luisa / Jastrzebska, Beata

Biomolecules

2020 Volume 10, Issue 6

Abstract: The pandemic associated with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV2) and its disease named COVID-19 challenged the scientific community to discover effective therapeutic solutions in a short period. Repurposing existing drugs is ... ...

Abstract	The pandemic associated with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV2) and its disease named COVID-19 challenged the scientific community to discover effective therapeutic solutions in a short period. Repurposing existing drugs is one viable approach that emphasizes speed during these urgent times. Famotidine, a class A G protein-coupled receptor antagonist used for the treatment of gastroesophageal reflux was recently identified in an in silico screening. Additionally, a recent retrospective clinical report showed that the treatment with famotidine provided a good outcome in patients infected with SARS-CoV2. A clinical trial testing effectiveness of famotidine in combination with hydroxychloroquine is currently ongoing in the United States (US). In the 1990s, famotidine was described as an antiviral agent against human immunodeficiency virus (HIV). Interestingly, some HIV protease inhibitors are presently being used against SARS-CoV2. However, it is not clear if famotidine could be effective against SARS-CoV2. Thus, by using a computational analysis, we aimed to examine if the antiviral effect of famotidine could be related to the inhibition of proteases involved in the virus replication. Our results showed that famotidine could interact within the catalytic site of the three proteases associated with SARS-CoV2 replication. However, weak binding affinity of famotidine to these proteases suggests that a successful famotidine therapy could likely be achieved only in combination with other antiviral drugs. Finally, analysis of famotidine's pharmacokinetic parameters indicated that its effect against SARS-CoV2 infection could be reached only upon intravenous administration. This work will contribute to the pharmacological knowledge of famotidine as an antiviral agent against SARS-CoV2.
MeSH term(s)	Administration, Intravenous ; Antiviral Agents/administration & dosage ; Antiviral Agents/pharmacokinetics ; Antiviral Agents/therapeutic use ; COVID-19 ; Computer Simulation ; Coronavirus Infections/drug therapy ; Drug Repositioning ; Famotidine/administration & dosage ; Famotidine/pharmacokinetics ; Famotidine/therapeutic use ; Humans ; Models, Molecular ; Molecular Docking Simulation ; Pandemics ; Pneumonia, Viral/drug therapy ; Protease Inhibitors/administration & dosage ; Protease Inhibitors/pharmacokinetics ; Protease Inhibitors/therapeutic use ; Receptors, G-Protein-Coupled/antagonists & inhibitors ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Protease Inhibitors ; Receptors, G-Protein-Coupled ; Famotidine (5QZO15J2Z8)
Keywords	covid19
Language	English
Publishing date	2020-06-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom10060954
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Article ; Online: Protective Effects of Flavonoids in Acute Models of Light-Induced Retinal Degeneration.

Ortega, Joseph T / Parmar, Tanu / Golczak, Marcin / Jastrzebska, Beata

Molecular pharmacology

2020 Volume 99, Issue 1, Page(s) 60–77

Abstract: Degeneration of photoreceptors caused by excessive illumination, inherited mutations, or aging is the principal pathology of blinding diseases. Pharmacological compounds that stabilize the visual receptor rhodopsin and modulate the cellular pathways ... ...

Abstract	Degeneration of photoreceptors caused by excessive illumination, inherited mutations, or aging is the principal pathology of blinding diseases. Pharmacological compounds that stabilize the visual receptor rhodopsin and modulate the cellular pathways triggering death of photoreceptors could avert this pathology. Interestingly, flavonoids can modulate the cellular processes, such as oxidative stress, inflammatory responses, and apoptosis, that are activated during retinal degeneration. As we found previously, flavonoids also bind directly to unliganded rod opsin, enhancing its folding, stability, and regeneration. In addition, flavonoids stimulate rhodopsin gene expression. Thus, we evaluated the effect of two main dietary flavonoids, quercetin and myricetin, in ATP-binding cassette subfamily A member 4
MeSH term(s)	Animals ; Electroretinography/methods ; Female ; Flavonoids/therapeutic use ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Neuroprotective Agents/therapeutic use ; Photic Stimulation/adverse effects ; Retinal Degeneration/etiology ; Retinal Degeneration/pathology ; Retinal Degeneration/prevention & control
Chemical Substances	Flavonoids ; Neuroprotective Agents
Language	English
Publishing date	2020-11-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/molpharm.120.000072
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Article ; Online: Class A G Protein-Coupled Receptor Antagonist Famotidine as a Therapeutic Alternative Against SARS-CoV2

Joseph T. Ortega / Maria Luisa Serrano / Beata Jastrzebska

Biomolecules, Vol 10, Iss 954, p

An In Silico Analysis

2020 Volume 954

Abstract	The pandemic associated with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV2) and its disease named COVID-19 challenged the scientific community to discover effective therapeutic solutions in a short period. Repurposing existing drugs is one viable approach that emphasizes speed during these urgent times. Famotidine, a class A G protein-coupled receptor antagonist used for the treatment of gastroesophageal reflux was recently identified in an in silico screening. Additionally, a recent retrospective clinical report showed that the treatment with famotidine provided a good outcome in patients infected with SARS-CoV2. A clinical trial testing effectiveness of famotidine in combination with hydroxychloroquine is currently ongoing in the United States (US). In the 1990s, famotidine was described as an antiviral agent against human immunodeficiency virus (HIV). Interestingly, some HIV protease inhibitors are presently being used against SARS-CoV2. However, it is not clear if famotidine could be effective against SARS-CoV2. Thus, by using a computational analysis, we aimed to examine if the antiviral effect of famotidine could be related to the inhibition of proteases involved in the virus replication. Our results showed that famotidine could interact within the catalytic site of the three proteases associated with SARS-CoV2 replication. However, weak binding affinity of famotidine to these proteases suggests that a successful famotidine therapy could likely be achieved only in combination with other antiviral drugs. Finally, analysis of famotidine’s pharmacokinetic parameters indicated that its effect against SARS-CoV2 infection could be reached only upon intravenous administration. This work will contribute to the pharmacological knowledge of famotidine as an antiviral agent against SARS-CoV2.
Keywords	antiviral therapy ; G protein-coupled receptor ; inhibitors ; proteases ; SARS-CoV2 ; Microbiology ; QR1-502 ; covid19
Subject code	616
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Flavonoids enhance rod opsin stability, folding, and self-association by directly binding to ligand-free opsin and modulating its conformation.

Ortega, Joseph T / Parmar, Tanu / Jastrzebska, Beata

The Journal of biological chemistry

2019 Volume 294, Issue 20, Page(s) 8101–8122

Abstract: Rhodopsin (Rho) is a visual G protein-coupled receptor expressed in the rod photoreceptors of the eye, where it mediates transmission of a light signal into a cell and converts this signal into a nerve impulse. More than 100 mutations in Rho are linked ... ...

Abstract	Rhodopsin (Rho) is a visual G protein-coupled receptor expressed in the rod photoreceptors of the eye, where it mediates transmission of a light signal into a cell and converts this signal into a nerve impulse. More than 100 mutations in Rho are linked to various ocular impairments, including retinitis pigmentosa (RP). Accordingly, much effort has been directed toward developing ligands that target Rho and improve its folding and stability. Natural compounds may provide another viable approach to such drug discovery efforts. The dietary polyphenol compounds, ubiquitously present in fruits and vegetables, have beneficial effects in several eye diseases. However, the underlying mechanism of their activity is not fully understood. In this study, we used a combination of computational methods, biochemical and biophysical approaches, including bioluminescence resonance energy transfer, and mammalian cell expression systems to clarify the effects of four common bioactive flavonoids (quercetin, myricetin, and their mono-glycosylated forms quercetin-3-rhamnoside and myricetrin) on rod opsin stability, function, and membrane organization. We observed that by directly interacting with ligand-free opsin, flavonoids modulate its conformation, thereby causing faster entry of the retinal chromophore into its binding pocket. Moreover, flavonoids significantly increased opsin stability, most likely by introducing structural rigidity and promoting receptor self-association within the biological membranes. Of note, the binding of flavonoids to an RP-linked P23H opsin variant partially restored its normal cellular trafficking. Together, our results suggest that flavonoids could be utilized as lead compounds in the development of effective nonretinoid therapeutics for managing RP-related retinopathies.
MeSH term(s)	Animals ; Binding Sites ; Cattle ; Cell Line ; Cell Membrane/chemistry ; Cell Membrane/genetics ; Cell Membrane/metabolism ; Flavonoids/chemistry ; Flavonoids/pharmacology ; Protein Folding/drug effects ; Protein Stability ; Protein Transport/drug effects ; Protein Transport/genetics ; Retinitis Pigmentosa/genetics ; Retinitis Pigmentosa/metabolism ; Rhodopsin/chemistry ; Rhodopsin/genetics ; Rhodopsin/metabolism
Chemical Substances	Flavonoids ; Rhodopsin (9009-81-8)
Language	English
Publishing date	2019-04-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA119.007808
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