On the cutting edge of proprotein convertase pharmacology: from molecular concepts to clinical applications

Abstract

There is increasing interest in the therapeutic targeting of proteases for the treatment of important diseases. Additionally new protein-based therapeutic strategies have the potential to widen the available treatments against these pathologies. In the last decade, accumulated evidence has confirmed that the family of proteases known as proprotein convertases (PCs) are potential targets for viral infections, osteoarthritis, cancer and cardiovascular disease, among others. Nevertheless, there are still many unanswered questions about the relevance of targeting PCs in a therapeutic context, especially regarding the anticipated secondary effects of treatment, considering the observed embryonic lethality of some PC knockout mice. In this review, the benefits of PCs as pharmacological targets will be discussed, with focus on concepts and strategies, as well as on the state of advancement of actual and future inhibitors.

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

“…The PCs have been loosely associated with malignancies because of their ability to enhance the activity of cancer-associated protein substrates, which are overexpressed by tumor cells, for example, members of the ADAM family of proteases, TGFb, MMPs, and insulin-like growth factor-1 receptor (IGF1R) family members (3). As PCs display increased expression in tumor cells and are required for enhanced processing to sustain tumorigenesis, they have been proposed as attractive antineoplastic targets (4). At this time, the evidence remains indirect as to how oncogenic control by the PCs is executed.…”

Furin as proprotein convertase and its role in normal and pathological biological processes

“…Основные даннные по ингибиторам фурина и ПК представлены в обзорах [15][16][17]. Ингибиторы фурина по химической природе можно разделить на белковые, пептидные, пептидоподобные или псевдопептидные и синтетические (ингибиторы непептидной природы) [18][19][20][21].…”

“…Однако внедрённых в клиническую практику препаратов не существует. Наиболее продвинутыми в контексте клинического применения являются исследования по использованию ингибиторов фурина и других ПК против бактериальных и вирусных инфекций, а также при онкологических заболеваниях [15,22,23]. Основные трудности по внедрению ингибиторов ПК в клинику связаны с их проницаемостью в клетки, так как многие исследования проведены на растворимой форме фурина, а также с недостаточными данными по профилю токсичности ингибиторов, возможными последствиями их действия для здоровья, влиянием на иммунную толерантность и выявленной летальностью эмбрионов у мышей [16,23,25].…”

Structural Determinants of Furin Inhibitors Derived from Influenza Hemagglutinin

“…Furin is responsible for posttranslational transformation and activation of proproteins into biologically active proteins and regulation of many physiological processes in living organisms [1]. In addition to their normal physiological role, furin and related convertases contribute to the maturation of many diseases-related proteins and are involved in tumorigenesis, neurodegenerative disorders, diabetes and atherosclerosis [2].…”