Broad-spectrum coronavirus 3C-like protease peptidomimetic inhibitors effectively block SARS-CoV-2 replication in cells: Design, synthesis, biological evaluation, and X-ray structure determination

Stefanelli, Irina; Corona, Angela; Cerchia, Carmen; Cassese, E; Improta, Salvatore; Costanzi, Elisa; Pelliccia, Sveva; Morasso, Stefano; Esposito, Francesca; Paulis, Annalaura; Scognamiglio, Sante; Leva, Francesco Saverio Di; Storici, Paola; Brindisi, Margherita; Tramontano, Enzo; Cannalire, Rolando; Summa, Vincenzo

doi:10.1016/j.ejmech.2023.115311

Cited by 9 publications

(9 citation statements)

References 37 publications

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“…The design and study of a related series of aldehyde-bearing compounds featuring various conformational locks actually reported that cyclopenta[ c ]pyrrole was amongst the most efficient pan-corona protease inhibitor in cellulo . 302 The dithia-7-azaspiro[4.4]nonane derivative 80 is a strong SARS-CoV-2 M pro inhibitor which was developed by Simcere Pharmaceutical. In association with ritonavir, 303 it has also been granted conditional market approval in China under the name Xiannuoxin/simnotrelvir 304–306 and the results of phase 1 clinical trials (NCT05339646) were reported recently.…”

Section: Inhibitors Of the Sars-cov-2 Main Proteasementioning

confidence: 99%

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

Janin

2024

RSC Med. Chem.

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Section: Inhibitors Of the Sars-cov-2 Main Proteasementioning

confidence: 99%

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

Janin

2024

RSC Med. Chem.

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“…Horphag Research (Limassol, Cyprus) has patented Pycnogenol ® for use in the treatment of endothelial dysfunction triggered by COVID-19. The extract contains 70-75% w/w proanthocyanidins as sources of polyphenolic compounds such as δ-(3,4-dihydroxyphenyl)-γ-valerolactone (7) and its 3-methoxy analog (8), diastereomeric catechins and epicatechins (9)(10)(11)(12), taxifolin (13), 4-hydroxybenzoic acid (8), protocatechuic acid (14), gallic acid (15), caffeic acid (16), and ferulic acid (17) (Figure 8), which can be used as therapies against COVID-19-related endothelial inflammation and/or endothelial systemic dysfunction. Moreover, the patent reports the employment of three daily doses of 50 mg of Pycnogenol ® as supplement therapy in subjects suffering from COVID-19.…”

Section: Polyphenolsmentioning

confidence: 99%

“…While respiratory transmission is the main method of spreading SARS-CoV-2, the dynamics of long COVID onset reveal a complex situation determined by multiple factors. As a matter of fact, the latter is a complex infection based on hidden interactions between the host immune system, viral persistence, and other variables [ 11 , 12 ]. Long COVID may be linked to persistent viral reservoirs or fragments in other tissues, raising concerns about possible transmission through physiological fluids or other pathways irrespective of the respiratory system.…”

Section: Introductionmentioning

confidence: 99%

Small Molecules for the Treatment of Long-COVID-Related Vascular Damage and Abnormal Blood Clotting: A Patent-Based Appraisal

Samarelli,

Graziano,

Gambacorta

et al. 2024

Viruses

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People affected by COVID-19 are exposed to, among others, abnormal clotting and endothelial dysfunction, which may result in deep vein thrombosis, cerebrovascular disorders, and ischemic and non-ischemic heart diseases, to mention a few. Treatments for COVID-19 include antiplatelet (e.g., aspirin, clopidogrel) and anticoagulant agents, but their impact on morbidity and mortality has not been proven. In addition, due to viremia-associated interconnected prothrombotic and proinflammatory events, anti-inflammatory drugs have also been investigated for their ability to mitigate against immune dysregulation due to the cytokine storm. By retrieving patent literature published in the last two years, small molecules patented for long-COVID-related blood clotting and hematological complications are herein examined, along with supporting evidence from preclinical and clinical studies. An overview of the main features and therapeutic potentials of small molecules is provided for the thromboxane receptor antagonist ramatroban, the pan-caspase inhibitor emricasan, and the sodium–hydrogen antiporter 1 (NHE-1) inhibitor rimeporide, as well as natural polyphenolic compounds.

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“…SARS-CoV-2 replication assay was performed as described [47]. Vero-E6 GFP cells were maintained in DMEM (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% v/v FBS (Gibco), 0.075% Na bicarbonate (7.5% solution, Gibco), and 1x Penstrep (Euroclone, Pero, Milan, Italy).…”

Section: Sars-cov-2 Viral Replication Assay In Vero-e6 Gfpmentioning

confidence: 99%

New Thiazolidine-4-One Derivatives as SARS-CoV-2 Main Protease Inhibitors

Messore,

Malune,

Patacchini

et al. 2024

Pharmaceuticals

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It has been more than four years since the first report of SARS-CoV-2, and humankind has experienced a pandemic with an unprecedented impact. Moreover, the new variants have made the situation even worse. Among viral enzymes, the SARS-CoV-2 main protease (Mpro) has been deemed a promising drug target vs. COVID-19. Indeed, Mpro is a pivotal enzyme for viral replication, and it is highly conserved within coronaviruses. It showed a high extent of conservation of the protease residues essential to the enzymatic activity, emphasizing its potential as a drug target to develop wide-spectrum antiviral agents effective not only vs. SARS-CoV-2 variants but also against other coronaviruses. Even though the FDA-approved drug nirmatrelvir, a Mpro inhibitor, has boosted the antiviral therapy for the treatment of COVID-19, the drug shows several drawbacks that hinder its clinical application. Herein, we report the synthesis of new thiazolidine-4-one derivatives endowed with inhibitory potencies in the micromolar range against SARS-CoV-2 Mpro. In silico studies shed light on the key structural requirements responsible for binding to highly conserved enzymatic residues, showing that the thiazolidinone core acts as a mimetic of the Gln amino acid of the natural substrate and the central role of the nitro-substituted aromatic portion in establishing π-π stacking interactions with the catalytic His-41 residue.

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Broad-spectrum coronavirus 3C-like protease peptidomimetic inhibitors effectively block SARS-CoV-2 replication in cells: Design, synthesis, biological evaluation, and X-ray structure determination

Cited by 9 publications

References 37 publications

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

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

Small Molecules for the Treatment of Long-COVID-Related Vascular Damage and Abnormal Blood Clotting: A Patent-Based Appraisal

New Thiazolidine-4-One Derivatives as SARS-CoV-2 Main Protease Inhibitors

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