Reprogramming of the Antibacterial Drug Vancomycin Results in Potent Antiviral Agents Devoid of Antibacterial Activity

Szűcs, Zsolt; Naesens, Lieve; Stevaert, Annelies; Ostorházi, Eszter; Batta, Gyula; Herczegh, Pál; Borbás, Anikó

doi:10.3390/ph13070139

Cited by 19 publications

(25 citation statements)

References 41 publications

(84 reference statements)

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“…Five μL lysate was transferred to a qPCR plate containing 9.75 μL of RT-qPCR mix (CellsDirect One-Step RT-qPCR) and 0.25 μL Superscript III RT/Platinum Taq enzyme, and HCoV-229E N-gene specific primers and probe. 52 The RT-qPCR protocol consisted of 15 min at 50°C; 2 min at 95°C; and 40 cycles of 15 s at 95°C and 45 s at 60°C. An N-gene plasmid standard was included to allow absolute quantification of viral RNA genome copies.…”

Section: Methodsmentioning

confidence: 99%

Betulonic acid derivatives inhibiting coronavirus replication in cell culture via the nsp15 endoribonuclease

Krasniqi

Stevaert

Loy

et al. 2020

Preprint

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The lack of medication to suppress coronavirus infections is a main reason for the dramatic course of the COVID-19 pandemic. There is an urgent need to identify suitable coronavirus drug targets and corresponding lead molecules. Here we describe the discovery of a class of coronavirus inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. SAR exploration of these 1,2,3-triazolo fused betulonic acid derivatives yielded lead molecule 5h as a strong inhibitor (antiviral EC50: 0.6 μM) of human coronavirus 229E replication. An nsp15 endoribonuclease active site mutant virus was markedly less sensitive to 5h, and selected resistance to the compound mapped to mutations in the N-terminal part of nsp15, at an interface between two nsp15 monomers. The biological findings were substantiated by the nsp15 binding mode for 5h, predicted by docking. Hence, besides delivering a distinct class of inhibitors, our study revealed a druggable pocket in the nsp15 hexamer with relevance for anti-coronavirus drug development.

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Section: Methodsmentioning

confidence: 99%

Betulonic acid derivatives inhibiting coronavirus replication in cell culture via the nsp15 endoribonuclease

Krasniqi

Stevaert

Loy

et al. 2020

Preprint

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“…Specifically, ligand-induced and -mediated reversible oligomerization of glycopeptide antibiotics is an interesting example of supramolecular structures, and formation of ligand-controlled peptide self-assemblies is challenging in their own right, which might even have a distant analogy with amyloid plaque formation [ 37 ]. Reprogramming or modulating the antimicrobial effects in vancomycin-type antibiotics with covalent modifications might be promising, since some glycopeptides were shown to have antiviral effects [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Bacterial Cell Wall Analogue Peptides Control the Oligomeric States and Activity of the Glycopeptide Antibiotic Eremomycin: Solution NMR and Antimicrobial Studies

et al. 2021

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For some time, glycopeptide antibiotics have been considered the last line of defense against Methicillin-resistant Staphylococcus aureus (MRSA). However, vancomycin resistance of Gram-positive bacteria is an increasingly emerging worldwide health problem. The mode of action of glycopeptide antibiotics is essentially the binding of peptidoglycan cell-wall fragments terminating in the d-Ala-d-Ala sequence to the carboxylate anion binding pocket of the antibiotic. Dimerization of these antibiotics in aqueous solution was shown to persist and even to enhance the antibacterial effect in a co-operative manner. Some works based on solid state (ss) Nuclear Magnetic Resonance (NMR) studies questioned the presence of dimers under the conditions of ssNMR while in a few cases, higher-order oligomers associated with contiguous back-to-back and face-to-face dimers were observed in the crystal phase. However, it is not proved if such oligomers persist in aqueous solutions. With the aid of 15N-labelled eremomycin using 15N relaxation and diffusion NMR methods, we observed tetramers and octamers when the N-Ac-d-Ala-d-Ala dipeptide was added. To the contrary, the N-Ac-d-Ala or (N-Ac)2-l-Lys-d-Ala-d-Ala tripeptide did not induce higher-order oligomers. These observations are interesting examples of tailored supramolecular self-organization. New antimicrobial tests have also been carried out with these self-assemblies against MRSA and VRE (resistant) strains.

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“…Yet, re-purposing antiviral drugs successfully is inherently dependent on the ability of an antiviral drug to be active against multiple viruses, hence, the need of a broad-spectrum antiviral effect. Historically, broad-spectrum antivirals have first been discovered by serendipity through simple screening assays against different viruses rather than through a deliberate strategy to design drugs to display a broad-spectrum antiviral effect [ 17 , 18 ] for ribavirin or more recently with antibiotic derivatives with antiviral properties [ 19 , 20 ]. From these initial antiviral drug evaluations emerged patterns of drugs with similar biological effects.…”

Section: The Interest Of Broad-spectrum Antiviral Strategiesmentioning

confidence: 99%

Broad-Spectrum Antiviral Strategies and Nucleoside Analogues

Geraghty

Aliota

Bonnac

2021

Viruses

108

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The emergence or re-emergence of viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus 1 and 2 (SARS and SARS-CoV-2) viruses, or new strains of influenza represents significant human health threats due to the absence of available treatments. Vaccines represent a key answer to control these viruses. However, in the case of a public health emergency, vaccine development, safety, and partial efficacy concerns may hinder their prompt deployment. Thus, developing broad-spectrum antiviral molecules for a fast response is essential to face an outbreak crisis as well as for bioweapon countermeasures. So far, broad-spectrum antivirals include two main categories: the family of drugs targeting the host-cell machinery essential for virus infection and replication, and the family of drugs directly targeting viruses. Among the molecules directly targeting viruses, nucleoside analogues form an essential class of broad-spectrum antiviral drugs. In this review, we will discuss the interest for broad-spectrum antiviral strategies and their limitations, with an emphasis on virus-targeted, broad-spectrum, antiviral nucleoside analogues and their mechanisms of action.

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Reprogramming of the Antibacterial Drug Vancomycin Results in Potent Antiviral Agents Devoid of Antibacterial Activity

Cited by 19 publications

References 41 publications

Betulonic acid derivatives inhibiting coronavirus replication in cell culture via the nsp15 endoribonuclease

Betulonic acid derivatives inhibiting coronavirus replication in cell culture via the nsp15 endoribonuclease

Bacterial Cell Wall Analogue Peptides Control the Oligomeric States and Activity of the Glycopeptide Antibiotic Eremomycin: Solution NMR and Antimicrobial Studies

Broad-Spectrum Antiviral Strategies and Nucleoside Analogues

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