ABSTRACT
Drug repositioning represents a cost- and time-efficient strategy for drug development. Here, we present a workflow of in silico screening of ACE2 enzymatic activators to treat COVID-19-induced metabolic complications. By using structure-based virtual screening and signature-based off-target effect identification via the Connectivity Map database, we provide a ranked list of the repositioning candidates as potential ACE2 enzymatic activators to ameliorate COVID-19-induced metabolic complications. The workflow can also be applied to other diseases with ACE2 as a potential target. For complete details on the use and execution of this protocol, please refer to Li et al. (2022).
Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2 , Enzyme Activators , High-Throughput Screening Assays , Humans , SARS-CoV-2Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Toll-Like Receptor 4/antagonists & inhibitors , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/metabolism , COVID-19/virology , Enzyme Activators/pharmacology , Enzyme Activators/therapeutic use , Humans , Inflammation/drug therapy , Inflammation/virology , Molecular Targeted Therapy , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Toll-Like Receptor 4/metabolismABSTRACT
The renin angiotensin system (RAS) plays an important role in the pathogenesis of variety of diseases. Targeting the formation and action of angiotensin II (Ang II), the main RAS peptide, has been the key therapeutic target for last three decades. ACE-related carboxypeptidase (ACE2), a monocarboxypeptidase that had been discovered 20 years ago, is one of the catalytically most potent enzymes known to degrade Ang II to Ang-(1-7), a peptide that is increasingly accepted to have organ-protective properties that oppose and counterbalance those of Ang II. In addition to its role as a RAS enzyme ACE2 is the main receptor for SARS-CoV-2. In this review, we discuss various strategies that have been used to achieve amplification of ACE2 activity including the potential therapeutic potential of soluble recombinant ACE2 protein and novel shorter ACE2 variants.
Subject(s)
Angiotensin-Converting Enzyme 2 , Antiviral Agents/therapeutic use , COVID-19 Drug Treatment , COVID-19/therapy , Genetic Therapy , Receptors, Virus , SARS-CoV-2/pathogenicity , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/therapeutic use , Animals , COVID-19/enzymology , COVID-19/genetics , COVID-19/virology , Enzyme Activation , Enzyme Activators/therapeutic use , Gene Amplification , Host-Pathogen Interactions , Humans , Receptors, Virus/genetics , Receptors, Virus/metabolism , Receptors, Virus/therapeutic use , Recombinant Proteins/therapeutic useABSTRACT
IRW (Ile-Arg-Trp) was identified as an inhibitor of angiotensin converting enzyme (ACE) from egg white protein ovotransferrin through an integrated in silico digestion and quantitative structure and activity relationship prediction in 2011. Oral administration of IRW to spontaneously hypertensive rats (SHRs) can significantly reduce blood pressure, via upregulation of ACE2, but not through the inhibition of ACE. ACE2 converts Ang II into Ang (1-7), thus lowering blood pressure via Mas receptor (MasR); coinfusion of Mas receptor antagonist A779 and IRW in SHRs abolished blood pressure-lowering effect of IRW, supporting a key role of ACE2/Ang (1-7)/MasR axis. Our ongoing study further established new roles of IRW as an antioxidant, an anti-inflammatory agent, an insulin sensitizer, and a bone cell anabolic. Future studies are warranted to understand the unique structure features of this peptide, its mechanisms of action at various targets, its bioavailability and metabolism, and its possible roles toward COVID-19.