NAAE (N- (2-Aminoethly)-1 aziridineethanamine) is a potent angiotensin-converting enzyme two (2) inhibitor. Huentelman et al. in 2004 identified this inhibitor molecule during a molecular docking study.
.jpg)
Figure 1: Structure of N- (2-Aminoethly)-1 aziridineethanamine (NAAE).
Angiotensin-converting enzyme 2 is considered an important therapeutic target for cardiovascular diseases and severe acute respiratory syndrome (SARS and SARS-Cov-2 – COVID19) outbreaks.
Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor targeted by the SARS coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2), which is the cause for the epidemic COVID-19.
Yan et al. recently reported the structure of the full-length human ACE2 in complex with the receptor-binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2 at a resolution of 2.9 Å, but with a 3.5 Å resolution at the ACE2-RBD interface. The structure showed that the extracellular peptidase domain of ACE2 recognizes the RBD and that an ACE2 dimer can accommodate two S protein trimers. According to Yan et al., the structural model suggests a model for the interaction of the spike protein with ACE2 by simultaneous binding of two S protein trimers to one ACE2 dimer.
Angiotensin-converting enzyme (ACE) is a highly glycosylated, transmembrane protein occurring in two differently spliced forms with similar but not identical substrate specificity. ACE acts as a carboxypeptidase. ACE removes the C-terminal dipeptide from angiotensin I (DRVYIHPFHL) to form angiotensin II (DRVYIHPF). However, unlike ACE, ACE2 removes a single C-terminal amino acid from angiotensin II to generate angiotensin-(1-7; DRVYIHP), or, with less efficiency, from angiotensin I to form angiotensin-(1-9; DRVYIHPFH). Studies found that ACE2 is not affected by classical ACE inhibitors. There appears to be a close interplay between ACE, ACE2, and peptides such as apelin and neurotensin.
The infection strategy of a coronavirus is complex. The SARS-CoV spike glycoprotein recognizes ACE2 as a receptor on the cell surface. During entering the cytoplasm, the virus core particle containing the genomic RNA bound to the nucleoprotein is released. The 5'-two-thirds of the genomic RNA is translated by the host's ribosomes generating the virus replicase polyprotein. The replicase attaches to the 3'-end of the input genome and begins replication of a full-length anti-genome and synthesizes negative-strand subgenomic RNAs. These RNAs serve as templates for a synthesis for new genomic RNA and viral subgenomic mRNAs (sgRNAs). All coronavirus mRNAs have a conserved 5'-end and are 3'-co-terminal and polyadenylated. However, to clarify the exact mechanism, more research will be needed. The release of the virus occurs after processing and assembly of virus particles in the Golgi apparatus and rough endoplasmic reticulum. Also, coronaviruses appear to use nuclear factors for the replication process. For more detail, see Turner et al. 2004.
In the search for a molecule that inhibits the interaction between ACE2 and the coronavirus Spike protein, Huentelman et al. used a molecular docking study for the identification of the ACE2 inhibitor molecule NAAE.
Reference
Matthew J. Huentelman, Jasenka Zubcevic, Jose A. Hernández Prada, Xiaodong Xiao, Dimiter S. Dimitrov, Mohan K. Raizada, and David A. Ostrov ; Structure-Based Discovery of a Novel Angiotensin-Converting Enzyme 2 Inhibitor. Hypertension. 2004;44:903–906.
Anthony J Turner, Julian A Hiscox, Nigel M Hooper; ACE2: from vasopeptidase to SARS virus receptor. Trends in Pharmacological Sciences. 25,6, 291-294, 2004.
---...---