東華大學圖書館 |

Language: English

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

Discovery of Chemical Tools for Podo...

Morgan, Paul,

FindBook

Google Book

Amazon

博客來

Discovery of Chemical Tools for Podocyte Protection in Glomerular Diseases /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Discovery of Chemical Tools for Podocyte Protection in Glomerular Diseases // Paul Morgan.
作者:	Morgan, Paul,
面頁冊數:	1 electronic resource (126 pages)
附註:	Source: Dissertations Abstracts International, Volume: 87-05, Section: B.
Contained By:	Dissertations Abstracts International87-05B.
標題:	Pharmaceutical sciences. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=32280515
ISBN:	9798297991156

Discovery of Chemical Tools for Podocyte Protection in Glomerular Diseases /
Morgan, Paul,

Discovery of Chemical Tools for Podocyte Protection in Glomerular Diseases /Paul Morgan. - 1 electronic resource (126 pages)

Source: Dissertations Abstracts International, Volume: 87-05, Section: B.

Proteinuric kidney diseases, such as focal segmental glomerulosclerosis (FSGS), are a leading cause of chronic kidney disease and end-stage renal failure, driven primarily by podocyte injury and detachment from the glomerular basement membrane. Current therapies rely largely on nonspecific immunosuppressants with limited efficacy and substantial off-target toxicity. This dissertation aimed to develop a structure-guided framework to discover small-molecule modulators of the intermediate-conductance calcium-activated potassium channel, KCa3.1, as a podocyte-protective strategy. Using high-resolution cryo-EM and X-ray structures, an allosteric site at the CaM/S4-S5 helix interface of KCa3.1 was targeted for large-scale virtual screening of over 3.5 million lead-like compounds. Computational prioritization yielded 26 diverse candidates that were synthesized and evaluated using a two-tiered assay platform combining high-throughput thallium (Tl⁺) flux screening and confirmatory whole-cell patch-clamp electrophysiology. Twelve compounds demonstrated activity, including seven activators and five inhibitors. Lead optimization through scaffold hopping produced second-generation modulators (D1-D4), among which compound D4 exhibited improved potency and favorable selectivity over related SK1 and BK channels. Functional assays in YAP-knockdown podocytes which is a model of impaired calcium handling showed that KCa3.1 activators such as BT-563 restored calcium homeostasis, supporting their potential for podocyte protection.This work establishes a computational and experimental pipeline for discovering ion channel modulators and identifies multiple novel KCa3.1 small molecule modulators with therapeutic relevance. Beyond revealing the feasibility of targeting the CaM/S4-S5 interface, the study provides foundational tools for rational drug design and sets the stage for translational studies in human kidney organoids and disease models. Taken together, these findings advance both the mechanistic understanding of KCa3.1 modulation and the development of mechanism-based tool compounds for proteinuric kidney diseases, with broader implications for calcium signaling driven disorders.

English

ISBN: 9798297991156Subjects--Topical Terms:

3173021
Pharmaceutical sciences.
Subjects--Index Terms:

Drug design

Discovery of Chemical Tools for Podocyte Protection in Glomerular Diseases /
LDR:03786nmm a22004573i 4500 001 2438141
005 20251130221841.5
006 m o d
007 cr|nu||||||||
008 261011s2025 miu||||||m |||||||eng d
020 $a 9798297991156
035 $a (MiAaPQD)AAI32280515
035 $a AAI32280515
040 $a MiAaPQD $b eng $c MiAaPQD $e rda
100 1 $a Morgan, Paul, $e author. $0 (orcid)0000-0002-3231-0738 $3 3829356
245 1 0 $a Discovery of Chemical Tools for Podocyte Protection in Glomerular Diseases / $c Paul Morgan.
264 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2025
300 $a 1 electronic resource (126 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertations Abstracts International, Volume: 87-05, Section: B.
500 $a Advisors: Campbell, Kirk; Schlessinger, Avner Committee members: Lazarus, Michael; Daehn, Ilse; Azeloglu, Evren; Osman, Roman; Jaimes, Edgar.
502 $b Ph.D. $c Icahn School of Medicine at Mount Sinai $d 2025.
520 $a Proteinuric kidney diseases, such as focal segmental glomerulosclerosis (FSGS), are a leading cause of chronic kidney disease and end-stage renal failure, driven primarily by podocyte injury and detachment from the glomerular basement membrane. Current therapies rely largely on nonspecific immunosuppressants with limited efficacy and substantial off-target toxicity. This dissertation aimed to develop a structure-guided framework to discover small-molecule modulators of the intermediate-conductance calcium-activated potassium channel, KCa3.1, as a podocyte-protective strategy. Using high-resolution cryo-EM and X-ray structures, an allosteric site at the CaM/S4-S5 helix interface of KCa3.1 was targeted for large-scale virtual screening of over 3.5 million lead-like compounds. Computational prioritization yielded 26 diverse candidates that were synthesized and evaluated using a two-tiered assay platform combining high-throughput thallium (Tl⁺) flux screening and confirmatory whole-cell patch-clamp electrophysiology. Twelve compounds demonstrated activity, including seven activators and five inhibitors. Lead optimization through scaffold hopping produced second-generation modulators (D1-D4), among which compound D4 exhibited improved potency and favorable selectivity over related SK1 and BK channels. Functional assays in YAP-knockdown podocytes which is a model of impaired calcium handling showed that KCa3.1 activators such as BT-563 restored calcium homeostasis, supporting their potential for podocyte protection.This work establishes a computational and experimental pipeline for discovering ion channel modulators and identifies multiple novel KCa3.1 small molecule modulators with therapeutic relevance. Beyond revealing the feasibility of targeting the CaM/S4-S5 interface, the study provides foundational tools for rational drug design and sets the stage for translational studies in human kidney organoids and disease models. Taken together, these findings advance both the mechanistic understanding of KCa3.1 modulation and the development of mechanism-based tool compounds for proteinuric kidney diseases, with broader implications for calcium signaling driven disorders.
546 $a English
590 $a School code: 1734
650 4 $a Pharmaceutical sciences. $3 3173021
650 4 $a Medicine. $3 641104
650 4 $a Bioinformatics. $3 553671
650 4 $a Biochemistry. $3 518028
653 $a Drug design
653 $a Focal segmental glomerulosclerosis
653 $a Ion channels
653 $a Podocytes
653 $a Virtual screening
690 $a 0572
690 $a 0564
690 $a 0487
690 $a 0715
710 2 $a Icahn School of Medicine at Mount Sinai. $b Biomedical Sciences. $e degree granting institution. $3 3829357
720 1 $a Campbell, Kirk $e degree supervisor.
720 1 $a Schlessinger, Avner $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 87-05B.
790 $a 1734
791 $a Ph.D.
792 $a 2025
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=32280515