Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19 (original) (raw)
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A potent SARS coronavirus (CoV) 3CL protease inhibitor (TG-0205221, K i ) 53 nM) has been developed. TG-0205221 showed remarkable activity against SARS CoV and human coronavirus (HCoV) 229E replications by reducing the viral titer by 4.7 log (at 5 µM) for SARS CoV and 5.2 log (at 1.25 µM) for HCoV 229E. The crystal structure of TG-0205221 (resolution ) 1.93 Å) has revealed a unique binding mode comprising a covalent bond, hydrogen bonds, and numerous hydrophobic interactions. Structural comparisons between TG-0205221 and a natural peptide substrate were also discussed. This information may be applied toward the design of other 3CL protease inhibitors.
Journal of Medicinal Chemistry, 2006
Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (M pro ), a protein required for the maturation of SARS-CoV, is vital for its life cycle, making it an attractive target for structure-based drug design of anti-SARS drugs. The structure-based virtual screening of a chemical database containing 58 855 compounds followed by the testing of potential compounds for SARS-CoV M pro inhibition leads to two hit compounds. The core structures of these two hits, defined by the docking study, are used for further analogue search. Twenty-one analogues derived from these two hits exhibited IC 50 values below 50 µM, with the most potent one showing 0.3 µM. Furthermore, the complex structures of two potent inhibitors with SARS-CoV M pro were solved by X-ray crystallography. They bind to the protein in a distinct manner compared to all published SARS-CoV M pro complex structures. They inhibit SARS-CoV M pro activity via intensive H-bond network and hydrophobic interactions, without the formation of a covalent bond. Interestingly, the most potent inhibitor induces protein conformational changes, and the inhibition mechanisms, particularly the disruption of catalytic dyad (His41 and Cys145), are elaborated. A[I] ) A[0] × {1 -[[I]/([I] + IC 50 )]} 5160
Journal of Medicinal Chemistry
Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CL pro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CL pro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CL pro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks. ■ INTRODUCTION Coronaviruses (CoV's) make up a family of enveloped positive-strand RNA pathogenic viruses that can cause acute and chronic conditions, including central nervous system disorders, the common cold, lower respiratory tract infections, and diarrhea. 1 The 229E and OC43 strains were among the first characterized human CoV strains starting in 1965. 2 The novel severe acute respiratory syndrome CoV reported in 2003, 3,4 now identified as SARS-CoV-1, became the first global human CoV pandemic leading to progressive respiratory failure in more than 8000 individuals and 916 deaths (fatality rate of 10−15%). 5 In the eight years that followed, significantly less lethal human coronaviruses NL64 and HKU1 were identified and characterized. 6,7 Subsequently, in 2012 SARSlike MERS (Middle East respiratory syndrome) was identified and found to have a low transmission rate, but significant lethality with a total of 2567 patients with confirmed infection worldwide, of which 882 (34% fatality) died from 2012 through February 2, 2021. To date, most confirmed MERS cases have been reported from Saudi Arabia. 8 Like the SARS-CoV of 2003 and MERS of 2012, the ongoing novel SARS-CoV pandemic of 2020, known as SARS-CoV-2, the causative agent of COVID-19, presents a worldwide threat due to its ability to rapidly spread person to person via respiratory droplets and its remarkable capacity to suppress human immune surveillance. 9 Unfortunately, SARS-CoV-2 has been much more extensive than MERS and SARS CoV-1 in its spread, with current worldwide infections, as of March 29, 2021, exceeding 126 million confirmed cases of COVID-19 and 2,778,619 confirmed deaths (fatality rate of ∼2%) according to the World Health Organization (WHO). 10 SARS-CoV-2 11 encodes multiple enzymes that are essential for viral replication. 12,13 As potential therapeutic antiviral targets, the two cysteine proteases, the chymotrypsin-like or main protease (3CL pro or M pro) and the papain-like protease (PL pro), have garnered significant attention. 14−16 Both SARS-CoV-1 and-CoV-2 genomes encode a large polyprotein that is proteolytically processed by these respective cysteine proteases. In solution, 3CL pro exists primarily as a dimer and has
ACS Pharmacology & Translational Science, 2021
SARS-CoV-2 main protease (M pro) is a cysteine protease that mediates the cleavage of viral polyproteins and is a validated antiviral drug target. M pro is highly conserved among all seven human coronaviruses, with certain M pro inhibitors having broad-spectrum antiviral activity. In this study, we designed two hybrid inhibitors UAWJ9-36-1 and UAWJ9-36-3 based on the superimposed X-ray crystal structures of SARS-CoV-2 M pro with GC-376, telaprevir, and boceprevir. Both UAWJ9-36-1 and UAWJ9-36-3 showed potent binding and enzymatic inhibition against the M pro 's from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-NL63, HCoV-229E, and HCoV-HKU1. Cell-based Flip-GFP M pro assay results show that UAWJ9-36-1 and UAWJ9-36-3 inhibited the intracellular protease activity of SARS-CoV-2 M pro. In addition, UAWJ9-36-1 and UAWJ9-36-3 had potent antiviral activity against SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E, with UAWJ9-36-3 being more potent than GC-376 in inhibiting SARS-CoV-2. Selectivity profiling revealed that UAWJ9-36-1 and UAWJ9-36-3 had an improved selectivity index over that of GC-376 against host cysteine proteases calpain I and cathepsin L, but not cathepsin K. The X-ray crystal structures of SARS-CoV-2 M pro with UAWJ9-36-1 and UAWJ9-36-3 were both solved at 1.9 Å, which validated our design hypothesis. Overall, hybrid inhibitors UAWJ9-36-1 and UAWJ9-36-3 are promising candidates to be further developed as broadspectrum coronavirus antivirals.
Lead compounds for the development of SARS-CoV-2 3CL protease inhibitors
Nature Communications, 2021
We report the identification of three structurally diverse compounds – compound 4, GC376, and MAC-5576 – as inhibitors of the SARS-CoV-2 3CL protease. Structures of each of these compounds in complex with the protease revealed strategies for further development, as well as general principles for designing SARS-CoV-2 3CL protease inhibitors. These compounds may therefore serve as leads for the basis of building effective SARS-CoV-2 3CL protease inhibitors.
A Speedy Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors
2020
The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2MPro) to digest two of its translated polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replication in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1MPro), we have designed and synthesized a series of SC2MPro inhibitors that contain β-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2MPro active site cysteine C145. All inhibitors display high potency with IC50 values at or below 100 nM. The most potent compound MPI3 has as an IC50 value as 8.5 nM. Crystallographic analyses of SC2MPro bound to 7 inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accomm...
Structure-based identification of potential SARS-CoV-2 main protease inhibitors
Journal of Biomolecular Structure and Dynamics, 2020
To address coronavirus disease (COVID-19), currently, no effective drug or vaccine is available. In this regard, molecular modeling approaches are highly useful to discover potential inhibitors of the main protease (M pro) enzyme of SARS-CoV-2. Since, the M pro enzyme plays key roles in mediating viral replication and transcription; therefore, it is considered as an attractive drug target to control SARS-CoV-2 infection. By using structure-based drug design, pharmacophore modeling, and virtual high throughput drug screening combined with docking and all-atom molecular dynamics simulation approach, we have identified five potential inhibitors of SARS-CoV-2 M pro. MD simulation studies revealed that compound 54035018 binds to the M pro with high affinity (DG bind À37.40 kcal/mol), and the complex is more stable in comparison with other protein-ligand complexes. We have identified promising leads to fight COVID-19 infection as these compounds fulfill all drug-likeness properties. However, experimental and clinical validations are required for COVID-19 therapy.
Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease
Frontiers in Chemistry
The Coronavirus disease-19 (COVID-19) pandemic is still devastating the world causing significant social, economic, and political chaos. Corresponding to the absence of globally approved antiviral drugs for treatment and vaccines for controlling the pandemic, the number of cases and/or mortalities are still rising. Current patient management relies on supportive treatment and the use of repurposed drugs as an indispensable option. Of a crucial role in the viral life cycle, ongoing studies are looking for potential inhibitors to the main protease (Mpro) of severe acute respiratory syndrome Coronavirus -2 (SARS-CoV-2) to tackle the pandemic. Although promising results have been achieved in searching for drugs inhibiting the Mpro, work remains to be done on designing structure-based improved drugs. This review discusses the structural basis of potential inhibitors targeting SARS-CoV-2 Mpro, identifies gaps, and provides future directions. Further, compounds with potential Mpro based an...
Review on development of potential inhibitors of SARS-CoV-2 main protease (M Pro
Future Journal of Pharmaceutical Sciences, 2022
Background: The etiological agent for the coronavirus illness outbreak in 2019-2020 is a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (COVID-19), whereas coronavirus disease pandemic of 2019 (COVID-19) has compelled the implementation of novel therapeutic options. Main body of the abstract: There are currently no targeted therapeutic medicines for this condition, and effective treatment options are quite restricted; however, new therapeutic candidates targeting the viral replication cycle are being investigated. The primary protease of the severe acute respiratory syndrome coronavirus 2 virus is a major target for therapeutic development (M Pro). Severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus (MERS-CoV) all seem to have a structurally conserved substrate-binding domain that can be used to develop novel protease inhibitors. Short conclusion: With the recent publication of the X-ray crystal structure of the severe acute respiratory syndrome coronavirus 2 Mm, virtual and in vitro screening investigations to find M Pro inhibitors are fast progressing. The focus of this review is on recent advancements in the quest for small-molecule inhibitors of the severe acute respiratory syndrome coronavirus 2 main protease.
Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors
Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro> has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in design and synthesis which led to submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.