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Drugs of the Kallikrein-Kinin System
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Drugs of the Kallikrein-Kinin System

A special issue of Drugs and Drug Candidates (ISSN 2813-2998). This special issue belongs to the section "Medicinal Chemistry and Preliminary Screening".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 6285

Special Issue Editor

Dr. François Marceau

E-Mail Website
Guest Editor
Department of Microbiology, Infectious Disease and Immunology, Faculty of Medicine, Université Laval, Québec, QC, Canada
Interests: ligands of G protein coupled receptors; receptors for peptide hormones (including bradykinin, anaphylatoxin C5a, neurokinins...); in vitro and in vivo pharmacology (NOT in silico docking); quantitative assessment of drug antagonism; peptides and peptidomimetics developed as drugs

Special Issue Information

Dear Colleagues,

The new MDPI journal Drugs and Drug Candidates is exploring the interest of the kinin community for a Special Issue under the title “Drugs of the Kallikrein–Kinin System”. Many recent and exciting therapeutic developments in the field justify this editorial project. Notably, various novel strategies are being developed to inhibit the formation of bradykinin or block its receptors in the management of hereditary angioedema. Several other applications are currently being investigated. Harnessing controlled kinin formation is also of potential therapeutic interest, as shown by the clinical development of recombinant tissue kallikrein for ischemic stroke and renal disease. Original research papers or review papers are welcome for submission to this Special Issue. Submissions will be rigorously peer-reviewed.

Dr. François Marceau
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. Drugs and Drug Candidates is an international peer-reviewed open access quarterly 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 1000 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

  • bradykinin
  • kallikrein
  • kinin
  • contact system
  • B1 and B2 bradykinin receptors
  • kininases
  • hereditary angioedema
  • angiotensin converting enzyme inhibitors

Published Papers (4 papers)

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Review

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14 pages, 2596 KiB  
Review
Sebetralstat: A Rapidly Acting Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema
by Edward P. Feener, Rebecca L. Davie, Nivetha Murugesan, Stephen J. Pethen, Sally L. Hampton, Michael D. Smith, Paul K. Audhya and Chris M. Yea
Drugs Drug Candidates 2024, 3(2), 328-341; https://doi.org/10.3390/ddc3020019 - 07 Apr 2024
Viewed by 577
Abstract
Sebetralstat is a novel, potent, and selective oral plasma kallikrein inhibitor drug candidate in clinical development for the on-demand treatment of hereditary angioedema (HAE). Upon binding, sebetralstat induces a conformational change in the active site of plasma kallikrein, which contributes to its high [...] Read more.
Sebetralstat is a novel, potent, and selective oral plasma kallikrein inhibitor drug candidate in clinical development for the on-demand treatment of hereditary angioedema (HAE). Upon binding, sebetralstat induces a conformational change in the active site of plasma kallikrein, which contributes to its high potency (Ki 3 nM) and selectivity (>1500 fold) against other serine proteases. Its physiochemical properties promote both rapid dissolution in the stomach and rapid absorption in the upper intestine that contribute to its fast and efficient absorption. A single oral administration of sebetralstat rapidly provides near-complete inhibition of plasma kallikrein and blockade of high-molecular-weight kininogen cleavage as early as 15 min, which drives its clinical efficacy. In a phase 2 clinical trial, sebetralstat significantly reduced the time to beginning of symptom relief (p < 0.0001) with median times of 1.6 h (95% CI: 1.5–3.0) with sebetralstat versus 9.0 h (4.0–17.2) with placebo. KONFIDENT (NCT05259917) is a phase 3 clinical trial assessing the on-demand use of sebetralstat for HAE. If successful, this trial could support the approval of sebetralstat as the first noninvasive, on-demand treatment option to rapidly halt HAE attacks and provide fast symptom relief. Full article
(This article belongs to the Special Issue Drugs of the Kallikrein-Kinin System)
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20 pages, 2033 KiB  
Review
Bradykinin-Mediated Angioedema Induced by Commonly Used Cardiovascular Drugs
by Janina Hahn, Jens Greve, Murat Bas and Georg Kojda
Drugs Drug Candidates 2023, 2(3), 708-727; https://doi.org/10.3390/ddc2030036 - 08 Sep 2023
Viewed by 2027
Abstract
ACE inhibitors, sartans, and sacubitril are among the most important drugs for the prevention of cardiovascular mortality and morbidity. At the same time, they are known to cause non-allergic bradykinin-mediated angioedema, a potentially fatal swelling of the mucosa and/or submucosa and deeper skin [...] Read more.
ACE inhibitors, sartans, and sacubitril are among the most important drugs for the prevention of cardiovascular mortality and morbidity. At the same time, they are known to cause non-allergic bradykinin-mediated angioedema, a potentially fatal swelling of the mucosa and/or submucosa and deeper skin without signs of urticaria or pruritus, occurring mainly in the head and neck region. In contrast with hereditary angioedema, which is also mediated by bradykinin, angioedema triggered by these drugs is by far the most common subtype of non-allergic angioedema. The molecular mechanisms underlying this type of angioedema, which are discussed here, are not yet sufficiently understood. There are a number of approved drugs for the prevention and treatment of acute attacks of hereditary angioedema. These include inhibitors of bradykinin synthesis that act as kallkrein inhibitors, such as the parenterally applied plasma pool, and recombinant C1 esterase inhibitor, ecallantide, lanadelumab, and the orally available berotralstat, as well as the bradykinin receptor type 2 antagonist icatibant. In contrast, no diagnostic tools, guidelines, or treatments have yet been approved for the diagnosis and treatment of acute non-allergic drug-induced angioedema, although it is more common and can take life-threatening courses. Approved specific drugs and a structured diagnostic workflow are needed for this emergency diagnosis. Full article
(This article belongs to the Special Issue Drugs of the Kallikrein-Kinin System)
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0 pages, 696 KiB  
Review
Drugs of the Kallikrein–Kinin System: An Overview
by François Marceau
Drugs Drug Candidates 2023, 2(3), 538-553; https://doi.org/10.3390/ddc2030028 - 05 Jul 2023
Cited by 1 | Viewed by 2829 | Correction
Abstract
The kallikrein–kinin system consists of the two kininogen substrates present in the blood plasma, and two serine proteases: the plasma and tissue kallikreins. The action of the latter on kininogens produces small peptides, the kinins, short-lived, but endowed by powerful pharmacologic actions on [...] Read more.
The kallikrein–kinin system consists of the two kininogen substrates present in the blood plasma, and two serine proteases: the plasma and tissue kallikreins. The action of the latter on kininogens produces small peptides, the kinins, short-lived, but endowed by powerful pharmacologic actions on blood vessels and other tissues. Many recent and exciting therapeutic developments in the field are briefly summarized. Notably, various novel strategies are being clinically developed to inhibit the formation of bradykinin or block its receptors in the management of hereditary angioedema. The interventions include orally bioavailable drugs, biotechnological proteins, and gene therapy. These approaches are currently explored in a variety of other inflammatory and thrombotic disorders. Harnessing controlled kinin formation is also of potential therapeutic interest, as shown by the clinical development of recombinant tissue kallikrein for ischemic stroke and renal disease. The biomarkers of kinin-mediated disorders, frequently implicating edemas, include the consumption of kininogen(s), plasma kallikrein activity, and the detection of circulating kinin metabolites such as fragments BK1–5 and BK2–9. Novel opportunities to clinically apply the underexploited drugs of the kallikrein–kinin system are briefly reviewed. This personal perspective is offered by an observer of and a participant in drug characterization throughout the last four decades. Full article
(This article belongs to the Special Issue Drugs of the Kallikrein-Kinin System)
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1 pages, 166 KiB  
Correction
Correction: Marceau, F. Drugs of the Kallikrein–Kinin System: An Overview. Drugs Drug Candidates 2023, 2, 538–553
by François Marceau
Drugs Drug Candidates 2024, 3(1), 208; https://doi.org/10.3390/ddc3010012 - 22 Feb 2024
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Abstract
In the original publication [...] Full article
(This article belongs to the Special Issue Drugs of the Kallikrein-Kinin System)
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