Identification and evaluation of potent Middle East respiratory syndrome coronavirus (MERS-CoV) 3CL Pro inhibitors

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory illness with fever, cough and shortness of breath. Up to date, it has resulted in 1826 human infections, including 649 deaths. Analogous to picornavirus 3C protease (3C), 3C-like protease (3CL) is critical for initiation of the MERS-CoV replication cycle and is thus regarded as a validated drug target. As presented here, our peptidomimetic inhibitors of enterovirus 3C (6b, 6c and 6d) inhibited 3CL of MERS-CoV and severe acute respiratory syndrome coronavirus (SARS-CoV) with IC values ranging from 1.7 to 4.7 μM and from 0.2 to 0.7 μM, respectively. In MERS-CoV-infected cells, the inhibitors showed antiviral activity with EC values ranging from 0.6 to 1.4 μM, by downregulating the viral protein production in cells as well as reducing secretion of infectious viral particles into culture supernatants. They also suppressed other α- and β-CoVs from human and feline origin. These compounds exhibited good selectivity index (over 70 against MERS-CoV) and could lead to the development of broad-spectrum antiviral drugs against emerging CoVs and picornaviruses.

Identification of two antiviral inhibitors targeting 3C-like serine/3C-like protease of porcine reproductive and respiratory syndrome virus and porcine epidemic diarrhea virus

“…values were approximately 8.42 and 8.5, respectively) (Table 1). Interestingly, we observed that the EC 50 was higher than the IC 50 , which may be due to the presence of a membrane barrier or the high protease concentration (1 μM) used in the FRET assay, as previously reported (Kumar et al, 2017).…”

Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019‐nCoV

“…[40][41][42][43][44][45] However,a few low-nm-range inhibitors have been identified that can be used in combination with other protease-inhibitor therapies to help combat the virus. Many of the inhibitors are in the micromolar range in terms of binding to and inhibiting the two proteases.…”

“…[46] For the purposeo ft his section, the inhibitors will be divided into categories based on the proteases that are inhibited to stop the virus from taking controlo f the host cells. [42] This potency could be adequate to combat 2019-nCoV. These compoundsa re in the low-mm range in terms of inhibition, leaving room for furtherd evelopment.…”

“…In a FRET-baseda ctivity assay,t he IC 50 value of GC376a gainst recombinant SARS 3CLpro was found to be 4.9 times that against FIPV 3CLpro( 4.35 vs. 0.72 mm,r espectively). Arepresentation of the top CoV protease inhibitors providing ascaffold to perform SAR studies in termsofdesigning novel small-molecule protease inhibitors for 2019-nCoV [40][41][42][43][44][45]49] .3 CLpro-1, the most potent inhibitor,ish ighlighted. Figure 7.…”

Porcine epidemic diarrhea virus papain-like protease 2 can be noncompetitively inhibited by 6-thioguanine

“…Like other CoVs, PEDV depends on its own proteases, including main protease (M pro ) and papain-like protease (PL pro ) to cleave the polyprotein, and alpha CoVs have both papain-like protease 1 (PL1 pro ) and papain-like protease 2 (PL2 pro ) (Lee, 2015;Wojdyla et al, 2010). Polyprotein cleavage is required for viral maturation and thus these proteases are ideal antiviral targets (Bacha et al, 2008;Cheng et al, 2015;Chou T et al, 2008;Kumar et al, 2017;Lin et al, 2018;Park et al, 2012;Ratia et al, 2008;Wu et al, 2006). Furthermore, in contrast to highly variable spike proteins targeted by antibodies (Li et al, 2005(Li et al, , 2017; Wang et al, 2013;Wu et al, 2009), proteases with more conserved structure and catalytic function may serve as a general target across different CoVs Bailey-Elkin et al, 2014;Chou et al, 2014;Ho et al, 2015;Ratia et al, 2006;Yang et al, 2003).…”