Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV)

Dampalla, Chamandi S.; Miller, Matthew J.; Kim, Yun-Jeong; Zabiegala, Alexandria; Nguyen, Harry Nhat; Madden, Trent K.; Thurman, Hayden A.; Machen, Alexandra J.; Cooper, Anne; Liu, Lijun; Battaile, K.P.; Lovell, Scott; Chang, Kyeong‐Ok; Groutas, William C.

doi:10.1016/j.ejmech.2023.115376

Cited by 10 publications

(3 citation statements)

References 80 publications

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“…These compounds also inhibit cathepsin L with IC 50 s in the range of 0.01–0.5 μM (data not shown). As we , and others , have previously reported, inhibitors with P1 Gln surrogate exhibit potent inhibition of cathepsin L contributing to dual antiviral activity against SARS-CoV-2. …”

Section: Resultssupporting

confidence: 63%

“…R is a hydrophobic amino acid (Ala or Val) that is nestled in the S4 subsite. − Comparatively, MERS-CoV 3CL pro has a similar substrate specificity for a -A-B-Leu-Gln-Y sequence, where Y is a small amino acid such as Gly. A and B can be Thr or Val, and Thr, Val, Arg, or Lys, respectively. − Collectively, peptidomimetic inhibitors with a Gln surrogate as the P1 residue and a hydrophobic natural or unnatural amino acid as the P2 residue have been found to be highly potent, as shown by us − and others. − Recent reports from our group have focused on optimizing potency using design elements that extend toward the S3–S4 subsites and beyond due to favorable binding interactions and significant conformational shifts of flexible loops connecting residues 165–169 and 189–195 observed upon binding of inhibitors with the enzyme, ,,− which led to the identification of lead candidates with clinical potential. Herein, we report the structure-guided design, synthesis, and biochemical, crystallographic, and cell-based studies of variously substituted 2-pyrrolidone inhibitors of SARS-CoV-2 and MERS-CoV 3CL pro that exploit stereochemical and conformational effects to optimize enzyme–inhibitor interactions with the S3–S4 active site domains of the protease.…”

Section: Introductionmentioning

confidence: 90%

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Structure-Guided Design of Potent Coronavirus Inhibitors with a 2-Pyrrolidone Scaffold: Biochemical, Crystallographic, and Virological Studies

Dampalla,

Kim,

Zabiegala

et al. 2024

J. Med. Chem.

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Zoonotic coronaviruses are known to produce severe infections in humans and have been the cause of significant morbidity and mortality worldwide. SARS-CoV-2 was the largest and latest contributor of fatal cases, even though MERS-CoV has the highest case-fatality ratio among zoonotic coronaviruses. These infections pose a high risk to public health worldwide warranting efforts for the expeditious discovery of antivirals. Hence, we hereby describe a novel series of inhibitors of coronavirus 3CL pro embodying an N-substituted 2-pyrrolidone scaffold envisaged to exploit favorable interactions with the S3−S4 subsites and connected to an invariant Leu-Gln P2−P1 recognition element. Several inhibitors showed nanomolar antiviral activity in enzyme and cell-based assays, with no significant cytotoxicity. Highresolution crystal structures of inhibitors bound to the 3CL pro were determined to probe and identify the molecular determinants associated with binding, to inform the structure-guided optimization of the inhibitors, and to confirm the mechanism of action of the inhibitors.

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Section: Resultssupporting

confidence: 63%

Section: Introductionmentioning

confidence: 90%

Structure-Guided Design of Potent Coronavirus Inhibitors with a 2-Pyrrolidone Scaffold: Biochemical, Crystallographic, and Virological Studies

Dampalla,

Kim,

Zabiegala

et al. 2024

J. Med. Chem.

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“…Many analogues of GC376 (53) were reported, 185,260,261 such as compounds resulting from a "fluorine walk" on the benzyl moiety and/or its replacement by a substituted cyclohexyl, a bulkier adamentyl and even more elaborated substituents. 195,199,201,262,263 As an illustration of the "leeway" on this position, the difluorocyclohexyl-bearing analogue 57 was found to be effective against a mouse model of MERS coronavirus infection. 188 Moreover, a deuterated derivative of 50 was evaluated on a mouse model of SARS-CoV-2 infection but this analogue showed no real advantage.…”

Section: Rsc Medicinal Chemistry Reviewmentioning

confidence: 99%

On the origins of SARS-CoV-2 main protease inhibitors

Janin

2024

RSC Med. Chem.

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MERS-CoV-nsp5 expression in human epithelial BEAS 2b cells attenuates type I interferon production by inhibiting IRF3 nuclear translocation

Zhang,

Kandwal,

Fayne

et al. 2024

Cell. Mol. Life Sci.

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Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an enveloped, positive-sense RNA virus that emerged in 2012, causing sporadic cases and localized outbreaks of severe respiratory illness with high fatality rates. A characteristic feature of the immune response to MERS-CoV infection is low type I IFN induction, despite its importance in viral clearance. The non-structural proteins (nsps) of other coronaviruses have been shown to block IFN production. However, the role of nsp5 from MERS-CoV in IFN induction of human respiratory cells is unclear. In this study, we elucidated the role of MERS-CoV-nsp5, the viral main protease, in modulating the host’s antiviral responses in human bronchial epithelial BEAS 2b cells. We found that overexpression of MERS-CoV-nsp5 had a dose-dependent inhibitory effect on IFN-β promoter activation and cytokine production induced by HMW-poly(I:C). It also suppressed IFN-β promoter activation triggered by overexpression of key components in the RIG-I-like receptor (RLR) pathway, including RIG-I, MAVS, IKK-ε and IRF3. Moreover, the overexpression of MERS-CoV-nsp5 did not impair expression or phosphorylation of IRF3, but suppressed the nuclear translocation of IRF3. Further investigation revealed that MERS-CoV-nsp5 specifically interacted with IRF3. Using docking and molecular dynamic (MD) simulations, we also found that amino acids on MERS-CoV-nsp5, IRF3, and KPNA4 may participate in protein-protein interactions. Additionally, we uncovered protein conformations that mask the nuclear localization signal (NLS) regions of IRF3 and KPNA4 when interacting with MERS-CoV-nsp5, suggesting a mechanism by which this viral protein blocks IRF3 nuclear translocation. Of note, the IFN-β expression was restored after administration of protease inhibitors targeting nsp5, indicating this suppression of IFN-β production was dependent on the enzyme activity of nsp5. Collectively, our findings elucidate a mechanism by which MERS-CoV-nsp5 disrupts the host’s innate antiviral immunity and thus provides insights into viral pathogenesis. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-024-05458-y.

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Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV)

Cited by 10 publications

References 80 publications

Structure-Guided Design of Potent Coronavirus Inhibitors with a 2-Pyrrolidone Scaffold: Biochemical, Crystallographic, and Virological Studies

Structure-Guided Design of Potent Coronavirus Inhibitors with a 2-Pyrrolidone Scaffold: Biochemical, Crystallographic, and Virological Studies

On the origins of SARS-CoV-2 main protease inhibitors

MERS-CoV-nsp5 expression in human epithelial BEAS 2b cells attenuates type I interferon production by inhibiting IRF3 nuclear translocation

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