Rhinoviruses are the pathogens most responsible for the common cold, even are a frequent cause of exacerbations in asthma, chronic and, obstructive pulmonary disease.
It belongs to the Picornaviridae family which contains other human or animal pathogens, such as poliovirus (PV), foot-and-mouth disease virus (FMDV), coxsackievirus, and hepatitis A virus.
NMT transfers myristate from (Myr-CoA) to the N-terminus of a range of proteins during protein translation. Additionally, this process exists across all eukaryotic species. For example, NMT proteins (NMT1 and NMT2) expresses in many tissues in humans.
VP0 in many picornaviruses is N-myristoylated by host cell N-myristoyltransferase (NMT). Furthermore, VP0 N-myristoylation plays an important role in capsid assembly and infectivity. Therefore, the host NMT may start to become an attractive antiviral drug target.
In this article, we will introduce a dual human NMT1/2 inhibitor with improvement in potency, IMP-1088.
IMP-1088 is a potent human N-myristoyltransferases NMT1 and NMT2 dual inhibitor with IC50s of <1 nM for HsNMT1 and HsNMT2. IMP-1088 has a Kd of <210 pM for HsNMT1. IMP-1088 efficiently blocks rhinovirus replication by blocking rhinovirus virus-encoded protein (VP0) N-myristoylation. IMP-1088 protects host cells from the cytotoxic effects of viral infection.
Additionally, IMP-1088 prevents virus-induced cytopathic effect (CPE) in a dose-dependent manner with an IC50 of 17 nM. Besides, it (at 125 nM) completely suppresses a new infectious virus with an IC50 of 5.8 nM.
In primary human bronchial epithelial cells (hBEC) with rhinovirus RV-A1 (MOI 5), IMP-1088 (1-1000 nM) blocks the production of infectious viruses and inhibits single-cycle replication.
In HeLa cells with rhinovirus RV-A16 (MOI 20), it inhibits the production of infectious rhinovirus particles by blocking virus assembly.
IMP-1088 potently blocks a key step in viral capsid assembly by inhibition of co-translational myristoylation of a specific virus-encoded protein (VP0). IMP-1088 blocks neither production of viral RNA, nor translation of rhinovirus polyprotein.
Reference:
Aurélie Mousnier, et al. Nat Chem. 2018 Jun;10(6):599-606.