The continuous spread of SARS-CoV-2 calls for more direct-acting antiviral agents to combat the highly infectious variants. The main protease (Mpro) is an promising target for anti-SARS-CoV-2 drug design. Here, we report the discovery of potent non-covalent non-peptide Mpro inhibitors featuring a 1,2,4-trisubstituted piperazine scaffold. We systematically modified the non-covalent hit MCULE-5948770040 by structure-based rational design combined with multi-site binding and privileged structure assembly strategies. The optimized compound GC-14 inhibits Mpro with high potency (IC50 = 0.40 μM) and displays excellent antiviral activity (EC50 = 1.1 μM), being more potent than Remdesivir. Notably, GC-14 exhibits low cytotoxicity (CC50 > 100 μM) and excellent target selectivity for SARS-CoV-2 Mpro (IC50 > 50 μM for cathepsins B, F, K, L, and caspase 3). X-ray co-crystal structures prove that the inhibitors occupy multiple subpockets by critical non-covalent interactions. These studies may provide a basis for developing a more efficient and safer therapy for COVID-19.

Discovery and Crystallographic Studies of Trisubstituted Piperazine Derivatives as Non-Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity and Low Toxicity

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication and transcription and represents an attractive drug target for fighting COVID-19. Many SARS-CoV-2 Mpro inhibitors have been reported, including covalent and noncovalent inhibitors. The SARS-CoV-2 Mpro inhibitor PF-07321332 (Nirmatrelvir) designed by Pfizer has been put on the market. This paper briefly introduces the structural characteristics of SARS-CoV-2 Mpro and summarizes the research progress of SARS-CoV-2 Mpro inhibitors from the aspects of drug repurposing and drug design. These information will provide a basis for the drug development of treating the infection of SARS-CoV-2 and even other coronaviruses in the future. 

The research progress of SARS-CoV-2 main protease inhibitors from 2020 to 2022

Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) identified in 2003 infected ∼8000 people in 26 countries with 800 deaths, which was soon contained and eradicated by syndromic surveillance and enhanced quarantine. A closely related coronavirus SARS-CoV-2, the causative agent of COVID-19 identified in 2019, has been dramatically more contagious and catastrophic. It has infected and caused various flu-like symptoms of billions of people in >200 countries, including >6 million people died of or with the virus. Despite the availability of several vaccines and antiviral drugs against SARS-CoV-2, finding new therapeutics is needed because of viral evolution and a possible emerging coronavirus in the future. The main protease (Mpro) of these coronaviruses plays important roles in their life cycle and is essential for the viral replication. This article represents a comprehensive review of the function, structure and inhibition of SARS-CoV and -CoV-2 Mpro, including structure-activity relationships, protein-inhibitor interactions and clinical trial status. 

Structure and function of SARS-CoV and SARS-CoV-2 main proteases and their inhibition: A comprehensive review.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10074736

COVID-19 therapeutics: Small-molecule drug development targeting SARS-CoV-2 main protease

In spite of the increasing number of biologics license applications, the development of covalent inhibitors is still a growing field within drug discovery. The successful approval of some covalent protein kinase inhibitors, such as ibrutinib (BTK covalent inhibitor) and dacomitinib (EGFR covalent inhibitor), and the very recent discovery of covalent inhibitors for viral proteases, such as boceprevir, narlaprevir, and nirmatrelvir, represent a new milestone in covalent drug development. Generally, the formation of covalent bonds that target proteins can offer drugs diverse advantages in terms of target selectivity, drug resistance, and administration concentration. The most important factor for covalent inhibitors is the electrophile (warhead), which dictates selectivity, reactivity, and the type of protein binding (i.e., reversible or irreversible) and can be modified/optimized through rational designs. Furthermore, covalent inhibitors are becoming more and more common in proteolysis, targeting chimeras (PROTACs) for degrading proteins, including those that are currently considered to be ‘undruggable’. The aim of this review is to highlight the current state of covalent inhibitor development, including a short historical overview and some examples of applications of PROTAC technologies and treatment of the SARS-CoV-2 virus.

Recent Advances in Covalent Drug Discovery

The main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure–activity relationships of novel small-molecule thioesters as SARS-CoV-2 Mpro inhibitors. Compounds 3w and 3x exhibited excellent SARS-CoV-2 Mpro inhibition with kinac/Ki of 58,700 M–1 s–1 (Ki = 0.0141 μM) and 27,200 M–1 s–1 (Ki = 0.0332 μM), respectively. In Calu-3 and Vero76 cells, compounds 3h, 3i, 3l, 3r, 3v, 3w, and 3x displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of 3w and 3af with SARS-CoV-2 Mpro was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the Mpro of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections.

https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.2c00636

Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure–Activity Relationships, Antiviral Activity, and X-ray Structure Determination

A new mild and practically simple alkyne hydroarylation protocol for the synthesis of 3‐(indol‐3‐yl)‐3‐(trifluoromethyl)acrylic acid esters by the reaction of indole derivatives with ethyl/methyl 4,4,4‐trifluoro‐3‐(indol‐3‐yl)but‐2‐enoates in trifluoroethanol was developed. This method has the following advantages: no catalyst, atom economy, high yields, broad substrate scope, and large‐scale synthesis. The potential application of this protocol was further demonstrated by the synthesis of a variety of CF3‐substituted synthons and a new class of (un)symmetrical 3,3ʹ‐diindolylmethanes with a quaternary carbon core that might be biologically active.

2,2,2‐Trifluoroethanol‐mediated hydroarylation of fluorinated alkynes with indoles: Application to diindolylmethanes

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Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure–Activity Relationships, Antiviral Activity, and X-ray Structure Determination

2,2,2‐Trifluoroethanol‐mediated hydroarylation of fluorinated alkynes with indoles: Application to diindolylmethanes