Design and Evaluation of a Novel Peptide–Drug Conjugate Covalently Targeting SARS-CoV-2 Papain-like Protease

Liu, Na; Zhang, Yichi; Lei, Yingshou; Wang, Rui; Zhan, Mei-Miao; Li, Jianbo; An, Yuhao; Zhou, Yaoqi; Zhan, Jian; Yin, Feng; Li, Zigang

doi:10.1021/acs.jmedchem.1c02022

Cited by 30 publications

(31 citation statements)

References 35 publications

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“…This approach to synthesize peptide-drug conjugates (PDCs) targeting SARS-CoV-2 PLpro appeared to improve on specificity toward the catalytic cysteine. Yet, these PDCs were still found to be nonselective for the other ten cysteines found in PLpro ( Liu et al, 2021a ). While peptide-based inhibitors remain an interesting avenue for development, the issues of their specificity for PLpro, and typically low oral bioavailability indicate that, as for Nirmatrelvir ( Owen et al, 2021 ), significant medicinal chemistry will be required to convert the peptidic features into more favourable drug-like properties.…”

Section: Overview Of the Plpro Inhibitor Binding Sitementioning

confidence: 96%

“…To improve on the efficacy of such inhibitors for PLpro, there have been recent attempts at combining the specificity of small molecules (such as GRL-0617 ) with the potency of covalent peptides or war heads ( Liu et al, 2021a ; Parks et al, 2021 ). In particular the latter manuscript, currently available as a preprint, discusses how GRL-0617 is derivatised to reach the catalytic Cys111, and a crystal structure shows that Leu162 indeed rotates again to open the congested channel typically observed in liganded PLpro structures.…”

Section: Overview Of the Plpro Inhibitor Binding Sitementioning

confidence: 99%

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Inhibitors of SARS-CoV-2 PLpro

2022

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The emergence of SARS-CoV-2 causing the COVID-19 pandemic, has highlighted how a combination of urgency, collaboration and building on existing research can enable rapid vaccine development to fight disease outbreaks. However, even countries with high vaccination rates still see surges in case numbers and high numbers of hospitalized patients. The development of antiviral treatments hence remains a top priority in preventing hospitalization and death of COVID-19 patients, and eventually bringing an end to the SARS-CoV-2 pandemic. The SARS-CoV-2 proteome contains several essential enzymatic activities embedded within its non-structural proteins (nsps). We here focus on nsp3, that harbours an essential papain-like protease (PLpro) domain responsible for cleaving the viral polyprotein as part of viral processing. Moreover, nsp3/PLpro also cleaves ubiquitin and ISG15 modifications within the host cell, derailing innate immune responses. Small molecule inhibition of the PLpro protease domain significantly reduces viral loads in SARS-CoV-2 infection models, suggesting that PLpro is an excellent drug target for next generation antivirals. In this review we discuss the conserved structure and function of PLpro and the ongoing efforts to design small molecule PLpro inhibitors that exploit this knowledge. We first discuss the many drug repurposing attempts, concluding that it is unlikely that PLpro-targeting drugs already exist. We next discuss the wealth of structural information on SARS-CoV-2 PLpro inhibition, for which there are now ∼30 distinct crystal structures with small molecule inhibitors bound in a surprising number of distinct crystallographic settings. We focus on optimisation of an existing compound class, based on SARS-CoV PLpro inhibitor GRL-0617, and recapitulate how new GRL-0617 derivatives exploit different features of PLpro, to overcome some compound liabilities.

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Section: Overview Of the Plpro Inhibitor Binding Sitementioning

confidence: 96%

Section: Overview Of the Plpro Inhibitor Binding Sitementioning

confidence: 99%

Inhibitors of SARS-CoV-2 PLpro

2022

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“…Liu et al reported the design of peptide–drug conjugates (PDCs) as covalent inhibitors of SARS-CoV-2 PL pro . 88 The PDCs consist of GRL0617 and cyclic sulfonium-containing peptides derived from PL pro substrate Leu-Arg-Gly-Gly ( Table 1 ). The sulfonium serves as a warhead and is designed to react with the C111.…”

Section: Sars-cov-2 Pl Pro Inhibitorsmentioning

confidence: 99%

Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

Tan

Jadhav

et al. 2022

J. Med. Chem.

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SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral polymerase inhibitors remdesivir and molnupiravir and the viral main protease inhibitor nirmatrelvir/ritonavir have been approved by the U.S. FDA. However, the emergence of variants of concern/interest calls for additional antivirals with novel mechanisms of action. The SARS-CoV-2 papain-like protease (PL pro ) mediates the cleavage of viral polyprotein and modulates the host’s innate immune response upon viral infection, rendering it a promising antiviral drug target. This Perspective highlights major achievements in structure-based design and high-throughput screening of SARS-CoV-2 PL pro inhibitors since the beginning of the pandemic. Encouraging progress includes the design of non-covalent PL pro inhibitors with favorable pharmacokinetic properties and the first-in-class covalent PL pro inhibitors. In addition, we offer our opinion on the knowledge gaps that need to be filled to advance PL pro inhibitors to the clinic.

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“…Co-crystal structures highlighted the key interactions with the protease and verified the covalent inhibition mechanism. Li and coworkers used 19 as the starting point for their covalent inhibitor and appended a sulfonium-tethered peptide to generate a peptide drug conjugate [ 147 ]. Both strategies incorporated the glycine residues of the PLpro substrates to navigate the S1 and S2 sites.…”

Section: Papain-like Protease (Plpro)mentioning

confidence: 99%

Antiviral Drug Discovery for the Treatment of COVID-19 Infections

Correia

Seagal

et al. 2022

Viruses

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The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting the vaccinated from infection, reducing the severity of disease, and deterring the transmission of infection. However, COVID-19 vaccination faces many challenges, such as the decline in vaccine-induced immunity over time, and the decrease in potency against some SARS-CoV-2 variants including the recently emerged Omicron variant, resulting in breakthrough infections. The challenges that COVID-19 vaccination is facing highlight the importance of the discovery of antivirals to serve as another means to tackle the pandemic. To date, neutralizing antibodies that block viral entry by targeting the viral spike protein make up the largest class of antivirals that has received US FDA emergency use authorization (EUA) for COVID-19 treatment. In addition to the spike protein, other key targets for the discovery of direct-acting antivirals include viral enzymes that are essential for SARS-CoV-2 replication, such as RNA-dependent RNA polymerase and proteases, as judged by US FDA approval for remdesivir, and EUA for Paxlovid (nirmatrelvir + ritonavir) for treating COVID-19 infections. This review presents an overview of the current status and future direction of antiviral drug discovery for treating SARS-CoV-2 infections, covering important antiviral targets such as the viral spike protein, non-structural protein (nsp) 3 papain-like protease, nsp5 main protease, and the nsp12/nsp7/nsp8 RNA-dependent RNA polymerase complex.

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Design and Evaluation of a Novel Peptide–Drug Conjugate Covalently Targeting SARS-CoV-2 Papain-like Protease

Cited by 30 publications

References 35 publications

Inhibitors of SARS-CoV-2 PLpro

Inhibitors of SARS-CoV-2 PLpro

Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

Antiviral Drug Discovery for the Treatment of COVID-19 Infections

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