Protease inhibitors targeting the main protease and papain-like protease of coronaviruses

Abstract

Introduction: The two cysteine proteases from the coronaviruses, which produced deadly outbreaks in the last two decades, SARS CoV-1/2 and MERS, the main protease (M pro) and the papain-like protease (PLP) are conserved among the three pathogens and started to be considered as exciting drug targets for developing antivirals. Areas covered: We review the drug design landscape in the scientific and patent literature to design peptidomimetic and non-peptidomimetic protease inhibitors (PIs) targeting these proteins. Expert opinion: The X-ray crystal structures of some of these proteases, alone and in complex with various inhibitors, were crucial for the discovery of effective such compounds, some of which also showed considerable antiviral activity and are considered preclinical candidates to fight these emerging infections, which in the case of Covid-19 already provoked an unprecedented worldwide pandemic.

Coronaviruses

“…This special issue of Expert Opinion on Therapeutic Patents dedicated to coronaviruses, addresses exactly this urgent need. The scientific and patent literature have been reviewed in a series of articles dealing with the drug repositioning for the search of new anti-CoV agents [25], RNA-dependent RNA polymerase (RdRp) inhibitors [26], helicase inhibitors [27] and inhibitors of the two cysteine proteases encoded in the genome of CoVs [28].…”

“…SARS-CoV-2 is an enveloped, positive-sense, singlestranded RNA beta-coronavirus, being prone to mutate very rapidly, since during RNA replication no error-correction mechanisms is used when copying the RNA genetic information into DNA [25][26][27][28]. Such mutations can confer new features to the virus, including the ability to infect new types of cells, or even new organisms and thus to determine the spillover, and this phenomenon occurred extensively in the case of SARS-CoV-2, as already mentioned here [11][12][13].…”

“…Like the preceding two CoVs that provoked outbreaks, SARS-CoV and MERS-CoV, the genome of SARS-CoV-2 encodes for several non-structural proteins (nsps), including several enzymes, such as an RNA-dependent RNA polymerase (RdRp), a helicase, a 3-chymotrypsin-like protease, also known as main protease (MPro) and a papain-like protease (PLP). These are in fact the main viral drug targets investigated up until now and considered in the review articles of this special issue [25][26][27][28].…”

“…These polypeptides are subsequently co-translationally cleaved into mature nsps through the activity of two proteases encoded in the 5′ region of the open reading frame 1 (ORF1), i.e. MPro and PLP [25][26][27][28]. There is a very high homology between each nsps (at the level of all four enzymes mentioned above, RdRp, helicase, MPro and PLP) of SARS-CoV-2, SARS-CoV, and MERS-CoV, which means that presumably effective inhibitors for one of them may act efficaciously for all three, and this is a rather relevant finding which should be attentively considered by scientists, drug companies and policy makers, because it may lead to the design of rather broad-acting antivirals [25][26][27][28].…”

Acriflavine, a clinically aproved drug, inhibits SARS-CoV-2 and other betacoronaviruses

“…The coronaviral genome encodes several structural and non-structural proteins (Knipe and Howley, 2013), including two cysteine proteases, M pro (nsp5) and PL pro (nsp3), essential for the virus replication (Shamsi et al, 2021). While extensive actions to identify inhibitors of M pro have been undertaken (Capasso et al, 2020), only scarce information is available for the PL pro .…”