Discovery and development of plasma kallikrein inhibitors for multiple diseases

Xie, Zhouling; Zhen, Li; Shao, Yanruisheng; Liao, Chenzhong

doi:10.1016/j.ejmech.2020.112137

Cited by 28 publications

(25 citation statements)

References 73 publications

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“…Lanadelumab (DX-2930) is a human IgG1 monoclonal antibody plasma kallikrein antagonist. 41,47,57 It is approved at a subcutaneously injected dose of 300 mg every 2 to 4 weeks. 47 Patients without breakthrough HAE attacks after 6 months can lengthen the interval to every 4 weeks.…”

Section: Overview Of Kallikrein Inhibitors Acute Therapymentioning

confidence: 99%

Specific Targeting of Plasma Kallikrein for Treatment of Hereditary Angioedema: A Revolutionary Decade

Busse

Kaplan

2022

The Journal of Allergy and Clinical Immunology: In Practice

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Hereditary angioedema (HAE) is a rare, chronic, genetic disease that presents with nonpruritic angioedema of the face, extremities, airway (can be life-threatening), genitourinary system, and abdomen. These symptoms can significantly impair daily activities. Hereditary angioedema is classified into HAE owing to a deficiency of functional C1INH (HAE-C1INH) or HAE with normal C1INH (HAE-nl-C1INH). Both type I and II HAE-C1INH result from inherited or spontaneous mutations in the SERPING1 gene, which encodes for C1INH. These mutations result in C1INH dysfunction, leading to uncontrolled plasma kallikrein activity with excessive bradykinin production. Bradykinin receptor activation leads to vasodilation, increased vascular permeability, and smooth muscle contractions, resulting in submucosal angioedema through fluid extravasation. Hereditary angioedema nl-C1INH is caused by either a known or unknown genetic mutation. The underlying mechanism of HAEnl-C1INH is less well understood but is thought to be related to bradykinin signaling. Plasma kallikrein inhibitors have been developed to inhibit the kallikrein-kinin pathway to prevent (prophylactic) and treat on-demand (acute) HAE attacks. Several of these medications are delivered through subcutaneous or intravenous injection, although new and emerging therapies include oral formulations. This article provides a historical review and describes the evolving landscape of available kallikrein inhibitors to treat HAE-C1INH.

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Section: Overview Of Kallikrein Inhibitors Acute Therapymentioning

confidence: 99%

Specific Targeting of Plasma Kallikrein for Treatment of Hereditary Angioedema: A Revolutionary Decade

Busse

Kaplan

2022

The Journal of Allergy and Clinical Immunology: In Practice

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“…The interindividual and ethnic variability of infectivity and the clinical outcome of Covid-19 pneumonia can most likely be explained by the various levels of ACE2 activity before and/or after the entry of coronavirus via ACE2 into the bronchoalveolar cells. In this respect it is interesting that the individual expression rate and pattern of ACE2 gen (genetic variants of ACE2 with different affinities for spike protein) seem to depend on gender, age and perhaps ethnic factors (higher in women, lower in elderly and higher in East Asians) [5]. However, very recent publications highlighted contradictions and methodological problems in some studies, and drew attention to the need of reinvestigation using extended and up-to-date methodology [36].…”

Section: Ras Dysregulationmentioning

confidence: 99%

“…Several cytokines were measured or suggested to contribute to the development of serious pulmonary inflammation [2][3][4] but no direct information is available on the plasma or tissue concentrations of bradykinin and kallidin (lysine-bradykinin), and their active metabolites (bradykinin-related peptides). The kallikrein-kinin system (KKS) is upregulated in many inflammatory diseases [5], and in the bronchoalveolar lavage fluid of COVID-19 patients [6]. Therefore, it seems reasonable to assume that the concentration of bradykinin peptides is markedly elevated in COVID-19 patients.…”

Section: Introductionmentioning

confidence: 99%

High-dose ACEi might be harmful in COVID-19 patients with serious respiratory distress syndrome by leading to excessive bradykinin receptor activation

Székács

Várbı́ró

Debreczeni

2021

PhysInt

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PurposeWe aimed to critically review the available information on the potential contribution of excessive kallikrein-kinin systems (KKSs) activation to severe respiratory inflammation in SARS-CoV-2 infection, and the likely consequence of ACE inhibition in seriously affected patients.MethodsThe literature related to the above topic was reviewed including papers that analysed the connections, actions, interactions, consequences and occasionally suggestions for rational interventions.Results/ConclusionSevere broncho-alveolar inflammation seems to be caused, at least in part, by upregulation of the KKS that increases plasma and/or local tissue concentrations of bradykinin (BK) in patients with COVID-19 infection. Besides KKS activation, suppression of ACE activity results in decreased bradykinin degradation, and these changes in concert can lead to excessive BK B1 and B2 receptor (BKB1R/BKB2R) activation. Aminopeptidase P (APP), and carboxypeptidase N also degrade bradykinin, but their protein expression and activity are unclear in COVID-19 infection. On the other hand, ACE2 expression is upregulated in patients with COVID-19 infection, so ACE2 activity is unlikely to be decreased despite blockade of part of ACE2 by the virus for entry into the cells. ACE2 cleaves lys-des-arginine9BK and arg-des-arginine9BK, the active metabolites of bradykinin, which stimulate the BKB1R receptor. Stimulation of BKB1R/BKB2R can exacerbate the pulmonary inflammatory response by causing vascular leakage and edema, vasodilation, smooth muscle spasm and stimulation of pain afferent nerves. Despite all uncertainties, it seems rational to treat comorbid COVID patients with serious respiratory distress syndrome with ARBs instead of high-dose ACE inhibitor (ACEi) that will further decrease bradykinin degradation and enhance BKB1R/BKB2R activation, but ACEi may not be contraindicated in patients with mild pulmonary symptoms.

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“…As a consequence, KLKB1 inhibitors are used to treat hereditary angioedema, microvascular complications of diabetes mellitus and cardiovascular disorders. Although in the latter case, under physiological conditions, KLKB1 has a cardioprotective effect, however, its increased plasma concentration or hyperactivity maintains cardiovascular pathology (Bhatwadekar et al., 2020; Hwang et al., 2019; Xie et al., 2020). Therefore, these pathological processes are the preferred targets for testing KLKB1 inhibitors in vivo.…”

Section: Compounds With Identified Molecular Targetsmentioning

confidence: 99%

Intrinsic drug potential of oxazolo[5,4‐d]pyrimidines and oxazolo[4,5‐d]pyrimidines

et al. 2021

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The oxazole and pyrimidine rings are widely displayed in natural products and synthetic molecules. They are known as the prime skeletons for drug discovery. On the account of structural and chemical diversity, oxazole and pyrimidine-based molecules, as central scaffolds, not only provide different types of interactions with various receptors and enzymes, showing broad biological activities, but also oc-How to cite this article:

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Discovery and development of plasma kallikrein inhibitors for multiple diseases

Cited by 28 publications

References 73 publications

Specific Targeting of Plasma Kallikrein for Treatment of Hereditary Angioedema: A Revolutionary Decade

Specific Targeting of Plasma Kallikrein for Treatment of Hereditary Angioedema: A Revolutionary Decade

High-dose ACEi might be harmful in COVID-19 patients with serious respiratory distress syndrome by leading to excessive bradykinin receptor activation

Intrinsic drug potential of oxazolo[5,4‐d]pyrimidines and oxazolo[4,5‐d]pyrimidines

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