Middle East respiratory syndrome coronavirus 3C-like proteinase (3CLpro)

Middle East respiratory syndrome coronavirus 3C-like proteinase (3CLpro), also known as the main protease (Mpro) or nsp5, is a key enzyme required for the maturation and replication of MERS-CoV [1.2.1, 1.2.2]. It is a cysteine protease that operates as a homodimer, utilizing a catalytic dyad composed of His41 and Cys148 to cleave the viral polyproteins pp1a and pp1ab at 11 conserved sites [1.2.5, 1.4.1]. This proteolytic processing releases essential non-structural proteins (nsps), such as the RNA-dependent RNA polymerase (nsp12) and helicase (nsp13), which are vital for the viral life cycle [1.1.1, 1.2.2]. Due to its indispensable role in viral replication and its unique substrate specificity—cleaving after a glutamine residue, a feature not shared by human proteases—3CLpro is a primary target for antiviral drug development [1.1.4, 1.3.2]. Inhibitors such as GC376, MK-7845, and various peptidomimetics are designed to bind the active site and block enzyme activity, thereby halting viral propagation [1.3.1, 1.3.4]. Therapeutic challenges include the potential for viral resistance through mutations and the need for effective delivery to infected tissues [1.1.4, 1.3.5].

Other names

Main protease [1.2.1]Mpro [1.2.2]nsp5 [1.2.5]3C-like protease [1.2.1]C30 endopeptidase [1.2.1]Coronavirus endopeptidase [1.2.1]

Cysteine protease inhibition via binding to the active site and blocking the catalytic Cys-His dyad, preventing the cleavage of viral polyproteins [1.2.1, 1.3.2].