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Biomolecules
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In Search of Selective High-Affinity Compounds to Inhibit Carbonic Anhydrases
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In Search of Selective High-Affinity Compounds to Inhibit Carbonic Anhydrases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (15 March 2020) | Viewed by 15378

Special Issue Editor

Prof. Daumantas Matulis

E-Mail Website
Guest Editor
Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, LT-10257 Vilnius, Lithuania
Interests: protein–ligand interaction; thermodynamics and kinetics of binding; structural aspects of the recognition and its application in drug design

Special Issue Information

Dear Colleagues,

Carbonic anhydrase (CA) is a fascinating enzyme that has been studied for over 80 years. Humans have 12 catalytically active, Zn-bearing isoforms of CA. Numerous drugs have been developed that target CAs. The enzyme has worked as a model protein for a large number of biochemical and biophysical studies. Isoform CA IX is highly overexpressed in numerous cancers making it a potential anticancer target for diagnostics and therapy. Despite ongoing clinical trials, no drug targeting CA IX has yet been approved as an anticancer agent.

I would like to invite you to submit papers to this special issue that would address any research topic from organic synthesis and characterization of novel compounds that bind CAs to the structural studies that describe novel compound binding to CAs all the way to the biological mechanism of CA IX and other isoforms play in cancer and other diseases. Any preclinical or clinical developments in the application of carbonic anhydrases as drug targets are welcome.

Prof. Daumantas Matulis
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • carbonic anhydrase
  • protein–ligand binding
  • thermodynamics
  • kinetics
  • drug design
  • anticancer

Published Papers (4 papers)

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Research

10 pages, 4583 KiB  
Article
Aspirin: A Suicide Inhibitor of Carbonic Anhydrase II
by Jacob Andring, Jacob Combs and Robert McKenna
Biomolecules 2020, 10(4), 527; https://doi.org/10.3390/biom10040527 - 31 Mar 2020
Cited by 10 | Viewed by 5999
Abstract
Carbonic anhydrase II (CAII) is a metalloenzyme that catalyzes the reversible hydration/dehydration of CO2/HCO3−. In addition, CAII is attributed to other catalytic reactions, including esterase activity. Aspirin (acetyl-salicylic acid), an everyday over-the-counter drug, has both ester and carboxylic [...] Read more.
Carbonic anhydrase II (CAII) is a metalloenzyme that catalyzes the reversible hydration/dehydration of CO2/HCO3−. In addition, CAII is attributed to other catalytic reactions, including esterase activity. Aspirin (acetyl-salicylic acid), an everyday over-the-counter drug, has both ester and carboxylic acid moieties. Recently, compounds with a carboxylic acid group have been shown to inhibit CAII. Hence, we hypothesized that Aspirin could act as a substrate for esterase activity, and the product salicylic acid (SA), an inhibitor of CAII. Here, we present the crystal structure of CAII in complex with SA, a product of CAII crystals pre-soaked with Aspirin, to 1.35Å resolution. In addition, we provide kinetic data to support the observation that CAII converts Aspirin to its deacetylated form, SA. This data may also explain the short half-life of Aspirin, with CAII so abundant in blood, and that Aspirin could act as a suicide inhibitor of CAII. Full article
(This article belongs to the Special Issue In Search of Selective High-Affinity Compounds to Inhibit Carbonic Anhydrases)
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11 pages, 8691 KiB  
Article
A Proof-of-Concept Fragment Screening of a Hit-Validated 96-Compounds Library against Human Carbonic Anhydrase II
by Steffen Glöckner, Andreas Heine and Gerhard Klebe
Biomolecules 2020, 10(4), 518; https://doi.org/10.3390/biom10040518 - 29 Mar 2020
Cited by 6 | Viewed by 2839
Abstract
Fragment screening is a powerful tool to identify and characterize binding pockets in proteins. We herein present the results of a proof-of-concept screening campaign of a versatile 96-entry fragment library from our laboratory against the drug target and model protein human carbonic anhydrase [...] Read more.
Fragment screening is a powerful tool to identify and characterize binding pockets in proteins. We herein present the results of a proof-of-concept screening campaign of a versatile 96-entry fragment library from our laboratory against the drug target and model protein human carbonic anhydrase II. The screening revealed a novel chemotype for carbonic anhydrase inhibition, as well as less common non-covalent interaction types and unexpected covalent linkages. Lastly, different runs of the PanDDA tool reveal a practical hint for its application. Full article
(This article belongs to the Special Issue In Search of Selective High-Affinity Compounds to Inhibit Carbonic Anhydrases)
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22 pages, 13730 KiB  
Article
The Influence of Varying Fluorination Patterns on the Thermodynamics and Kinetics of Benzenesulfonamide Binding to Human Carbonic Anhydrase II
by Steffen Glöckner, Khang Ngo, Björn Wagner, Andreas Heine and Gerhard Klebe
Biomolecules 2020, 10(4), 509; https://doi.org/10.3390/biom10040509 - 27 Mar 2020
Cited by 6 | Viewed by 3013
Abstract
The fluorination of lead-like compounds is a common tool in medicinal chemistry to alter molecular properties in various ways and with different goals. We herein present a detailed study of the binding of fluorinated benzenesulfonamides to human Carbonic Anhydrase II by complementing macromolecular [...] Read more.
The fluorination of lead-like compounds is a common tool in medicinal chemistry to alter molecular properties in various ways and with different goals. We herein present a detailed study of the binding of fluorinated benzenesulfonamides to human Carbonic Anhydrase II by complementing macromolecular X-ray crystallographic observations with thermodynamic and kinetic data collected with the novel method of kinITC. Our findings comprise so far unknown alternative binding modes in the crystalline state for some of the investigated compounds as well as complex thermodynamic and kinetic structure-activity relationships. They suggest that fluorination of the benzenesulfonamide core is especially advantageous in one position with respect to the kinetic signatures of binding and that a higher degree of fluorination does not necessarily provide for a higher affinity or more favorable kinetic binding profiles. Lastly, we propose a relationship between the kinetics of binding and ligand acidity based on a small set of compounds with similar substitution patterns. Full article
(This article belongs to the Special Issue In Search of Selective High-Affinity Compounds to Inhibit Carbonic Anhydrases)
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23 pages, 3341 KiB  
Article
New Monoclonal Antibodies for a Selective Detection of Membrane-Associated and Soluble Forms of Carbonic Anhydrase IX in Human Cell Lines and Biological Samples
by Dovile Stravinskiene, Aiste Imbrasaite, Vilma Petrikaite, Daumantas Matulis, Jurgita Matuliene and Aurelija Zvirbliene
Biomolecules 2019, 9(8), 304; https://doi.org/10.3390/biom9080304 - 25 Jul 2019
Cited by 11 | Viewed by 3147
Abstract
Monoclonal antibodies (MAbs) selectively targeting tumor-associated antigens such as carbonic anhydrase IX (CA IX) can significantly contribute to research, diagnostics, and treatment of CA IX-related cancers. CA IX is overexpressed in numerous hypoxic cancers where it promotes tumor progression. Therefore, it is considered [...] Read more.
Monoclonal antibodies (MAbs) selectively targeting tumor-associated antigens such as carbonic anhydrase IX (CA IX) can significantly contribute to research, diagnostics, and treatment of CA IX-related cancers. CA IX is overexpressed in numerous hypoxic cancers where it promotes tumor progression. Therefore, it is considered as a promising tumor biomarker. A novel collection of MAbs against recombinant CA IX was developed and evaluated in different immunoassays for studying CA IX expression. The reactivity of MAbs with native cell surface protein was confirmed by flow cytometry and the presence of hypoxia-inducible CA IX was investigated in several human cancer cell lines. In addition, the applicability of MAbs for visualization of CA IX-positive tumor cells by immunofluorescence microscopy was demonstrated. MAb H7 was identified as the most promising MAb for different immunoassays. It recognized a linear epitope covering CA IX sequence of 12 amino acid residues 55-GEDDPLGEEDLP-66 within the proteoglycan domain. The MAb H7 was the only one of the collection to immunoprecipitate CA IX protein from cell lysates and detect the denatured CA IX with near-infrared fluorescence Western blot. It was also employed in sandwich enzyme-linked immunosorbent assay to detect a soluble form of CA IX in growth medium of tumor cells and blood plasma samples. The diagnostic potential of the MAb H7 was confirmed on formalin-fixed and paraffin-embedded tissue specimen of cervical carcinoma in situ by immunohistochemistry. The generated MAbs, in particularly clone H7, have great potential in diagnostics and research of CA IX-related cancers. Full article
(This article belongs to the Special Issue In Search of Selective High-Affinity Compounds to Inhibit Carbonic Anhydrases)
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