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Article ; Online: Structural and functional complexity of HSP90 in cellular homeostasis and disease.

Chiosis, Gabriela / Digwal, Chander S / Trepel, Jane B / Neckers, Len

2023 Volume 24, Issue 11, Page(s) 797–815

Abstract: Heat shock protein 90 (HSP90) is a chaperone with vital roles in regulating proteostasis, long recognized for its function in protein folding and maturation. A view is emerging that identifies HSP90 not as one protein that is structurally and ... ...

Abstract	Heat shock protein 90 (HSP90) is a chaperone with vital roles in regulating proteostasis, long recognized for its function in protein folding and maturation. A view is emerging that identifies HSP90 not as one protein that is structurally and functionally homogeneous but, rather, as a protein that is shaped by its environment. In this Review, we discuss evidence of multiple structural forms of HSP90 in health and disease, including homo-oligomers and hetero-oligomers, also termed epichaperomes, and examine the impact of stress, post-translational modifications and co-chaperones on their formation. We describe how these variations influence context-dependent functions of HSP90 as well as its interaction with other chaperones, co-chaperones and proteins, and how this structural complexity of HSP90 impacts and is impacted by its interaction with small molecule modulators. We close by discussing recent developments regarding the use of HSP90 inhibitors in cancer and how our new appreciation of the structural and functional heterogeneity of HSP90 invites a re-evaluation of how we discover and implement HSP90 therapeutics for disease treatment.
MeSH term(s)	HSP90 Heat-Shock Proteins/metabolism ; Molecular Chaperones/metabolism ; Protein Folding ; Proteostasis ; Homeostasis
Chemical Substances	HSP90 Heat-Shock Proteins ; Molecular Chaperones
Language	English
Publishing date	2023-07-31
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2031313-5
ISSN	1471-0080 ; 1471-0072
ISSN (online)	1471-0080
ISSN	1471-0072
DOI	10.1038/s41580-023-00640-9
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Article: PET Molecular Imaging in Drug Development: The Imaging and Chemistry Perspective.

Nerella, Sridhar Goud / Singh, Priti / Sanam, Tulja / Digwal, Chander Singh

Frontiers in medicine

2022 Volume 9, Page(s) 812270

Abstract: Positron emission tomography with selective radioligands advances the drug discovery and development process by revealing information about target engagement, proof of mechanism, pharmacokinetic and pharmacodynamic profiles. Positron emission tomography ( ...

Abstract	Positron emission tomography with selective radioligands advances the drug discovery and development process by revealing information about target engagement, proof of mechanism, pharmacokinetic and pharmacodynamic profiles. Positron emission tomography (PET) is an essential and highly significant tool to study therapeutic drug development, dose regimen, and the drug plasma concentrations of new drug candidates. Selective radioligands bring up target-specific information in several disease states including cancer, cardiovascular, and neurological conditions by quantifying various rates of biological processes with PET, which are associated with its physiological changes in living subjects, thus it reveals disease progression and also advances the clinical investigation. This study explores the major roles, applications, and advances of PET molecular imaging in drug discovery and development process with a wide range of radiochemistry as well as clinical outcomes of positron-emitting carbon-11 and fluorine-18 radiotracers.
Language	English
Publishing date	2022-02-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2022.812270
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Article: Editorial: Development of selective carbon-11 radioligands for target-based PET molecular imaging in oncology, cardiology and neurology.

Nerella, Sridhar Goud / Kumar, Manoj / Solingapuram Sai, Kiran Kumar / Digwal, Chander Singh

Frontiers in medicine

2023 Volume 10, Page(s) 1137088

Language	English
Publishing date	2023-01-23
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2023.1137088
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Article: Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action.

Sharma, Sahil / Joshi, Suhasini / Kalidindi, Teja / Digwal, Chander S / Panchal, Palak / Lee, Sang-Gyu / Zanzonico, Pat / Pillarsetty, Nagavarakishore / Chiosis, Gabriela

Biomedicines

2023 Volume 11, Issue 10

Abstract: Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we ...

Abstract	Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. They have shown significant therapeutic value in cancer and neurodegenerative diseases by disassembling epichaperomes, which are assemblies of tightly bound chaperones and other factors that serve as scaffolding platforms to pathologically rewire protein-protein interactions. To investigate their impact on epichaperomes in vivo, we conducted pharmacokinetic and target occupancy measurements for zelavespib and monitored epichaperome assemblies biochemically in a mouse model. Our findings provide evidence of the intricate mechanism through which zelavespib modulates epichaperomes in vivo. Initially, zelavespib becomes trapped when epichaperomes bound, a mechanism that results in epichaperome disassembly, with no change in the expression level of epichaperome constituents. We propose that the initial trapping stage of epichaperomes is a main contributing factor to the extended on-target residence time observed for this agent in clinical settings. Zelavespib's residence time in tumors seems to be dictated by target disassembly kinetics rather than by frank drug-target unbinding kinetics. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases.
Language	English
Publishing date	2023-09-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11102599
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Article ; Online: How aberrant N-glycosylation can alter protein functionality and ligand binding: An atomistic view.

Castelli, Matteo / Yan, Pengrong / Rodina, Anna / Digwal, Chander S / Panchal, Palak / Chiosis, Gabriela / Moroni, Elisabetta / Colombo, Giorgio

Structure (London, England : 1993)

2023 Volume 31, Issue 8, Page(s) 987–1004.e8

Abstract: Protein-assembly defects due to an enrichment of aberrant conformational protein variants are emerging as a new frontier in therapeutics design. Understanding the structural elements that rewire the conformational dynamics of proteins and pathologically ... ...

Abstract	Protein-assembly defects due to an enrichment of aberrant conformational protein variants are emerging as a new frontier in therapeutics design. Understanding the structural elements that rewire the conformational dynamics of proteins and pathologically perturb functionally oriented ensembles is important for inhibitor development. Chaperones are hub proteins for the assembly of multiprotein complexes and an enrichment of aberrant conformers can affect the cellular proteome, and in turn, phenotypes. Here, we integrate computational and experimental tools to investigte how N-glycosylation of specific residues in glucose-regulated protein 94 (GRP94) modulates internal dynamics and alters the conformational fitness of regions fundamental for the interaction with ATP and synthetic ligands and impacts substructures important for the recognition of interacting proteins. N-glycosylation plays an active role in modulating the energy landscape of GRP94, and we provide support for leveraging the knowledge on distinct glycosylation variants to design molecules targeting GRP94 disease-associated conformational states and assemblies.
MeSH term(s)	Glycosylation ; Ligands ; Molecular Chaperones/chemistry ; Protein Conformation ; Protein Binding
Chemical Substances	Ligands ; Molecular Chaperones
Language	English
Publishing date	2023-06-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2023.05.017
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Article ; Online: Synthesis, biological evaluation and mechanistic studies of 4-(1,3-thiazol-2-yl)morpholine-benzimidazole hybrids as a new structural class of antimicrobials.

Aaghaz, Shams / Digwal, Chander S / Neshat, Naziya / Maurya, Indresh K / Kumar, Vinod / Tikoo, Kulbhushan / Jain, Rahul / Kamal, Ahmed

Bioorganic chemistry

2023 Volume 136, Page(s) 106538

Abstract: In spite of several attempts to develop newer pharmacophores as potential antimicrobial agents, the benzimidazole scaffold is still considered as one of the most sought after structural component towards the design of compounds that act against a wide ... ...

Abstract	In spite of several attempts to develop newer pharmacophores as potential antimicrobial agents, the benzimidazole scaffold is still considered as one of the most sought after structural component towards the design of compounds that act against a wide spectrum of microbes. Herein, we report the design and synthesis of a new structural class of 4-(1,3-thiazol-2-yl)morpholine-benzimidazole hybrids as antimicrobial agents. The most potent analog, 6g shows IC
MeSH term(s)	Humans ; Anti-Infective Agents ; Benzimidazoles/pharmacology ; Cryptococcus neoformans ; Cryptococcosis ; Candida albicans ; Morpholines ; Microbial Sensitivity Tests ; Antifungal Agents/pharmacology
Chemical Substances	Anti-Infective Agents ; Benzimidazoles ; Morpholines ; Antifungal Agents
Language	English
Publishing date	2023-04-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120080-x
ISSN	1090-2120 ; 0045-2068
ISSN (online)	1090-2120
ISSN	0045-2068
DOI	10.1016/j.bioorg.2023.106538
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Article ; Online: Synthesis of

Sharma, Sahil / Kalidindi, Teja / Joshi, Suhasini / Digwal, Chander S / Panchal, Palak / Burnazi, Eva / Lee, Sang Gyu / Pillarsetty, Nagavarakishore / Chiosis, Gabriela

STAR protocols

2022 Volume 3, Issue 2, Page(s) 101318

Abstract: Epichaperomes are disease-associated pathologic scaffolds composed of tightly bound chaperones and co-chaperones. They provide opportunities for precision medicine where aberrant protein-protein interaction networks, rather than a single protein, are ... ...

Abstract	Epichaperomes are disease-associated pathologic scaffolds composed of tightly bound chaperones and co-chaperones. They provide opportunities for precision medicine where aberrant protein-protein interaction networks, rather than a single protein, are detected and targeted. This protocol describes the synthesis and characterization of two
MeSH term(s)	Animals ; Iodine Radioisotopes ; Mice ; Neoplasms/pathology ; Protein Interaction Maps ; Tomography, X-Ray Computed
Chemical Substances	Iodine Radioisotopes ; Iodine-124
Language	English
Publishing date	2022-04-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2022.101318
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Article: Disease‐specific interactome alterations via epichaperomics: the case for Alzheimer’s disease

Ginsberg, Stephen D. / Neubert, Thomas A. / Sharma, Sahil / Digwal, Chander S. / Yan, Pengrong / Timbus, Calin / Wang, Tai / Chiosis, Gabriela

FEBS journal. 2022 Apr., v. 289, no. 8

2022

Abstract: The increasingly appreciated prevalence of complicated stressor‐to‐phenotype associations in human disease requires a greater understanding of how specific stressors affect systems or interactome properties. Many currently untreatable diseases arise due ... ...

Abstract	The increasingly appreciated prevalence of complicated stressor‐to‐phenotype associations in human disease requires a greater understanding of how specific stressors affect systems or interactome properties. Many currently untreatable diseases arise due to variations in, and through a combination of, multiple stressors of genetic, epigenetic, and environmental nature. Unfortunately, how such stressors lead to a specific disease phenotype or inflict a vulnerability to some cells and tissues but not others remains largely unknown and unsatisfactorily addressed. Analysis of cell‐ and tissue‐specific interactome networks may shed light on organization of biological systems and subsequently to disease vulnerabilities. However, deriving human interactomes across different cell and disease contexts remains a challenge. To this end, this opinion article links stressor‐induced protein interactome network perturbations to the formation of pathologic scaffolds termed epichaperomes, revealing a viable and reproducible experimental solution to obtaining rigorous context‐dependent interactomes. This article presents our views on how a specialized ‘omics platform called epichaperomics may complement and enhance the currently available conventional approaches and aid the scientific community in defining, understanding, and ultimately controlling interactome networks of complex diseases such as Alzheimer’s disease. Ultimately, this approach may aid the transition from a limited single‐alteration perspective in disease to a comprehensive network‐based mindset, which we posit will result in precision medicine paradigms for disease diagnosis and treatment.
Keywords	disease diagnosis ; epigenetics ; human diseases ; humans ; phenotype ; precision medicine ; protein-protein interactions
Language	English
Dates of publication	2022-04
Size	p. 2047-2066.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	REVIEW
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16031
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Article ; Online: Disease-specific interactome alterations via epichaperomics: the case for Alzheimer's disease.

Ginsberg, Stephen D / Neubert, Thomas A / Sharma, Sahil / Digwal, Chander S / Yan, Pengrong / Timbus, Calin / Wang, Tai / Chiosis, Gabriela

The FEBS journal

2021 Volume 289, Issue 8, Page(s) 2047–2066

Abstract: The increasingly appreciated prevalence of complicated stressor-to-phenotype associations in human disease requires a greater understanding of how specific stressors affect systems or interactome properties. Many currently untreatable diseases arise due ... ...

Abstract	The increasingly appreciated prevalence of complicated stressor-to-phenotype associations in human disease requires a greater understanding of how specific stressors affect systems or interactome properties. Many currently untreatable diseases arise due to variations in, and through a combination of, multiple stressors of genetic, epigenetic, and environmental nature. Unfortunately, how such stressors lead to a specific disease phenotype or inflict a vulnerability to some cells and tissues but not others remains largely unknown and unsatisfactorily addressed. Analysis of cell- and tissue-specific interactome networks may shed light on organization of biological systems and subsequently to disease vulnerabilities. However, deriving human interactomes across different cell and disease contexts remains a challenge. To this end, this opinion article links stressor-induced protein interactome network perturbations to the formation of pathologic scaffolds termed epichaperomes, revealing a viable and reproducible experimental solution to obtaining rigorous context-dependent interactomes. This article presents our views on how a specialized 'omics platform called epichaperomics may complement and enhance the currently available conventional approaches and aid the scientific community in defining, understanding, and ultimately controlling interactome networks of complex diseases such as Alzheimer's disease. Ultimately, this approach may aid the transition from a limited single-alteration perspective in disease to a comprehensive network-based mindset, which we posit will result in precision medicine paradigms for disease diagnosis and treatment.
MeSH term(s)	Alzheimer Disease/genetics ; Humans ; Phenotype ; Precision Medicine ; Proteins
Chemical Substances	Proteins
Language	English
Publishing date	2021-06-12
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16031
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Article ; Online: Chemical probes and methods for single-cell detection and quantification of epichaperomes in hematologic malignancies.

Merugu, Swathi / Sharma, Sahil / Kaner, Justin / Digwal, Chander / Sugita, Mayumi / Joshi, Suhasini / Taldone, Tony / Guzman, Monica L / Chiosis, Gabriela

Methods in enzymology

2020 Volume 639, Page(s) 289–311

Abstract: Detection of protein connectivity dysfunctions in biological samples, i.e., informing on how protein-protein interactions change from a normal to a disease state, is important for both biomedical research and clinical development. The epichaperome is an ... ...

Abstract	Detection of protein connectivity dysfunctions in biological samples, i.e., informing on how protein-protein interactions change from a normal to a disease state, is important for both biomedical research and clinical development. The epichaperome is an executor of protein connectivity dysfunction in disease, and thus a surrogate for its detection. This chapter will detail on published methods for epichaperome detection and quantification that combine the advantages of multiparameter flow cytometry with those of the PU-FITC fluorescently labeled epichaperome detection probe. It will offer a comprehensive method description that includes the synthesis and characterization of an epichaperome detection probe and of the negative control probe, the preparation of the biospecimen for epichaperome analysis, the execution of the epichaperome detection and quantification assay and lastly, the data acquisition and analysis. The method provides, at single-cell level, the functional signature of cells, differentiating itself from other single-cell methods that provide a catalog of molecules.
MeSH term(s)	Flow Cytometry ; Hematologic Neoplasms ; Humans
Language	English
Publishing date	2020-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1557-7988
ISSN (online)	1557-7988
DOI	10.1016/bs.mie.2020.04.057
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