What is Peptidase Family?

Peptidase is an enzyme that hydrolyzes peptide chains. They are an enzyme necessary for the survival of all living things, and the genes encoding peptidases account for 2% of all proteins encoded. In a survey of 500 individual peptidases,14% were found to be drug targets. Peptidases play important roles in many biological processes, including digestion of food proteins, intracellular protein cycling, the coagulation cascade system, antigen presentation, and activation of various proteins, including enzymes, peptide hormones, and neurotransmitters.

Peptidase Family is divided into 2 main classes including endopeptidase and exopeptidase.  

--Endopeptidase

Endopeptidase is a member of Peptidase Family. Fibroblast activation protein (FAP), a prolyl-cleaving endopeptidase proposed as an anti-cancer drug target, is a membrane protease that is highly expressed by cancer-associated fibroblasts (CAFs). FAP can modulate the tumor microenvironment (TME) by remodeling the extracellular matrix (ECM), and its overexpression on CAFs is associated with poor prognosis in various cancers. The TME is in part accountable for the limited efficacy of chimeric antigen receptor (CAR)-T cell therapy in treatment of solid tumors. Targeting FAP with CAR-T cells is one of the strategies being researched to overcome the challenges in the TME.

Figure 1 Anti-FAP CAR-T cells in the solid tumor TME

 (A) The anti-FAP CAR constructs consist of an anti-FAP targeting moiety (scFv), a spacer, a transmembrane domain (TM),

and signaling domains (CD28/41BB and CD3ζ). These are transduced and expressed on T cells. The developed

anti-FAP CAR-T cells can then bind to FAP expressed on CAFs.

(B) Binding of anti-FAP CAR-T cells to FAP on CAFs within the hostile, multicellular TME.

--Exopeptidase

Exopeptidase is a member of Peptidase Family. ACE2, belongs to exopeptidase, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted.

Figure 2 Transcriptional, post-transcriptional, and post-translational regulation of ACE2

Peptidase Family, the major targets for drug discovery, provides a new research idea for drug intervention therapy of Corona Virus Disease 2019 (COVID-19), cancers, etc.