Istaroxime and Beyond: New Therapeutic Strategies to Specifically Activate SERCA and Treat Heart Failure

Avvisato, Roberta; Jankauskas, Stanislovas S.; Santulli, Gaetano

doi:10.1124/jpet.122.001446

Cited by 5 publications

(2 citation statements)

References 31 publications

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“…Of all these SERCA2a activators only istaroxime, a known Na + /K + transporting ATPase inhibitor as well as an inotropic/lusitropic agent acting to enhance SERCA2a activity, has been in phase IIb clinical trials for treatment of heart failure 45,46 . However, because of its unsuitability for human usage (poor gastrointestinal absorption, high clearance rate, and extensive metabolic transformation) 46 , istaroxime derivatives were designed from QSAR studies and a new promising class of SERCA2a activators has been identified 47,48,49 .…”

Section: Discussionmentioning

confidence: 99%

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

Roopnarine

Yuen

Thompson

et al. 2023

Preprint

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We have used FRET-based biosensors in live cells, in a robust high-throughput screening (HTS) platform, to identify small-molecules that alter the structure and activity of the cardiac sarco/endoplasmic reticulum calcium ATPase (SERCA2a). Our primary aim is to discover drug-like small-molecule activators that improve SERCA's function for the treatment of heart failure. We have previously demonstrated the use of an intramolecular FRET biosensor, based on human SERCA2a, by screening a small validation library using novel microplate readers that can detect the fluorescence lifetime or emission spectrum with high speed, precision, and resolution. Here we report results from a 50,000-compound screen using the same biosensor, with hit compounds functionally evaluated using Ca2+-ATPase and Ca2+-transport assays. We focused on 18 hit compounds, from which we identified eight structurally unique compounds and four compound classes as SERCA modulators, approximately half of which are activators and half are inhibitors. While both activators and inhibitors have therapeutic potential, the activators establish the basis for future testing in heart disease models and lead development, toward pharmaceutical therapy for heart failure.

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Section: Discussionmentioning

confidence: 99%

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

Roopnarine

Yuen

Thompson

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

Roopnarine

Yuen

Thompson

et al. 2023

Preprint

View full text Add to dashboard Cite

We have used FRET-based biosensors in live cells, in a robust high-throughput screening (HTS) platform, to identify small-molecules that alter the structure and activity of the cardiac sarco/endoplasmic reticulum calcium ATPase (SERCA2a). Our primary aim is to discover drug-like small-molecule activators that improve SERCA’s function for the treatment of heart failure. We have previously demonstrated the use of an intramolecular FRET biosensor, based on human SERCA2a, by screening a small validation library using novel microplate readers that can detect the fluorescence lifetime or emission spectrum with high speed, precision, and resolution. Here we report results from a 50,000-compound screen using the same biosensor, with hit compounds functionally evaluated using Ca2+-ATPase and Ca2+-transport assays. We focused on 18 hit compounds, from which we identified eight structurally unique compounds and four compound classes as SERCA modulators, approximately half of which are activators and half are inhibitors. While both activators and inhibitors have therapeutic potential, the activators establish the basis for future testing in heart disease models and lead development, toward pharmaceutical therapy for heart failure.

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Moving theJournal of Pharmacology and Experimental TherapeuticsForward to Address the Needs of Our Authors and Editors—Editorial

Van Meerveld,

Levi,

Gross

et al. 2024

J Pharmacol Exp Ther

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Journal of Pharmacology and Experimental Therapeutics (JPET) is one of the leading journals serving the membership of the American Society for Pharmacology and Experimental Therapeutics (ASPET). JPET focuses on the publication of important and ground-breaking innovative science. We publish original research papers and minireviews dealing with interactions of chemicals with biologic systems. All aspects of pharmacology and therapeutics are within the scope of the Journal. Ensuring the highest scientific quality of JPET depends on the hard work of the editor-in-chief, senior associate editors, editorial advisory board members, and reviewers who give so much time to the journal. Effective, fair, and timely reviews of submitted manuscripts are critical for the vibrancy of JPET. We want to take this opportunity to thank all of you who have been involved in the JPET scientific manuscript review process by providing your expertise as a reviewer. Taken together, each of you has provided dedicated scientific service. It is also our pleasure to recognize Mahmood S. Mozaffari for his ASPET Best Reviewer Award. He handled many submissions efficiently and provided consistently high-quality, thoughtful, and constructive recommendation summaries to the authors.As we start the new year, we would like to share with you the latest additions to JPET that we hope will address the future needs of our authors and editors. We have addressed the need to improve the author experience and enhance experimental rigor and reproducibility by adding a simplified author checklist to promote experimental rigor and reproducibility (Table 1). New and Improved Article TypesViewpoint. We have introduced a new article type called Viewpoint (Greenwood-Van Meerveld, 2022) that was introduced to broaden the scientific content of JPET by inviting an author to present a new or unique perspective on a manuscript recently accepted for publication in JPET. The initial goal is to publish at least one Viewpoint per issue coupled with the editorialized article. Recently, due to the interest received, some issues will include two Viewpoints. Viewpoint articles may comment on existing problems, highlight current advances, and briefly speculate future directions of the topic or provide other points of view. The first Viewpoint by Avvisato et al. ( 2023) was published in January 2023.Minireviews. JPET continues to publish Minireviews as a platform for discussing concepts and topics of importance and relevance to pharmacology. Minireview submissions may be invited or unsolicited, and JPET encourages those interested in preparing a Minireview manuscript to complete a Presubmission Inquiry to determine whether the topic lies within the scope of the journal. The JPET Minireview guidelines for authors were revised and updated in July 2023 to provide additional guidance in preparing Minireview manuscripts. Page charges are waived for Minireview submissions.JPET recently launched a new Minireview initiative together with the ASPET Young Scientist Committee to foster the r...

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Istaroxime and Beyond: New Therapeutic Strategies to Specifically Activate SERCA and Treat Heart Failure

Cited by 5 publications

References 31 publications

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

Moving theJournal of Pharmacology and Experimental TherapeuticsForward to Address the Needs of Our Authors and Editors—Editorial

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