Hydrophobic Derivatives of Glycopeptide Antibiotics as Inhibitors of Protein Kinases

Cozza, Giorgio; Fortuna, Manuela; Meggio, Flavio; Sarno, Stefania; Kubbutat, Michael H.G.; Totzke, Frank; Schäechtele, Christoph; Pinna, Lorenzo A.; Olsufyeva, Eugenia N.; Preobrazhenskaya, M. N.

doi:10.1134/s0006297918100073

Cited by 3 publications

(5 citation statements)

References 29 publications

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“…Viral protein kinases have been shown to play a role in the viral infection cycle of hepatitis C virus, human immunodeficiency virus, and influenza viruses among others, particularly at the levels of viral entry and replication. It has been shown that teicoplanin and eremomycin derivatives are able to inhibit protein kinases, which could potentially explain a mechanism of the antiviral activity of these compounds against HIV, HCV, and influenza viruses . Hydrophobic aglycon derivatives of teicoplanin and eremomycin were tested against 12 human recombinant protein kinases and 2 rat liver protein kinases.…”

Section: Glycopeptides and Their Derivatives Against Gram-negative Ba...mentioning

confidence: 69%

“…It has been shown that teicoplanin and eremomycin derivatives are able to inhibit protein kinases, which could potentially explain a mechanism of the antiviral activity of these compounds against HIV, HCV, and influenza viruses. 126 Hydrophobic aglycon derivatives of teicoplanin and eremomycin were tested against 12 human recombinant protein kinases and 2 rat liver protein kinases. Three of the teicoplanin derivatives (71,72,73) substituted with carboxamides inhibited all of the human protein kinases tested at low concentrations (IC 50 s between 0.54 μM and 8.53 μM), except for 73 which had an IC 50 of 18.1 μM against one protein kinase (Figure 11).…”

Section: T H Imentioning

confidence: 99%

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Emerging Roles of Glycopeptide Antibiotics: Moving beyond Gram-Positive Bacteria

et al. 2021

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Glycopeptides, a class of cell wall biosynthesis inhibitors, have been the antibiotics of choice against drug-resistant Gram-positive bacterial infections. Their unique mechanism of action involving binding to the substrate of cell wall biosynthesis and substantial longevity in clinics makes this class of antibiotics an attractive choice for drug repurposing and reprofiling. However, resistance to glycopeptides has been observed due to alterations in the substrate, cell wall thickening, or both. The emergence of glycopeptide resistance has resulted in the development of synthetic and semisynthetic glycopeptide analogues to target acquired resistance. Recent findings demonstrate that these derivatives, along with some of the FDA approved glycopeptides have been shown to have antimicrobial activity against Gram-negative bacteria, Mycobacteria, and viruses thus expanding their spectrum of activity across the microbial kingdom. Additional mechanisms of action and identification of novel targets have proven to be critical in broadening the spectrum of activity of glycopeptides. This review focuses on the applications of glycopeptides beyond their traditional target group of Gram-positive bacteria. This will aid in making the scientific community aware about the nontraditional activity profiles of glycopeptides, identify the existing loopholes, and further explore this antibiotic class as a potential broadspectrum antimicrobial agent.

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Section: Glycopeptides and Their Derivatives Against Gram-negative Ba...mentioning

confidence: 69%

Section: T H Imentioning

confidence: 99%

Emerging Roles of Glycopeptide Antibiotics: Moving beyond Gram-Positive Bacteria

et al. 2021

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“…37 Another in vitro study also confirmed that various hydrophobic residues of teicoplanin aglycon carboxamides which were effective against PKs of SARS-COV, successfully inhibited all tested human PKs at low micromolar IC 50 values. 59 pneumoniae, among others, 60,61 and viruses such as influenza, rhinovirus/enterovirus, influenza B virus, and human immunodeficiency virus 62 are commonly identified in SARS-COV2 respiratory infections. These bacterial pathogens cause infections in up to 7.1% of COVID-19 cases, and have led to the empiric use of broad spectrum antibiotics in the majority of patients (71.3%).…”

Section: Figure 1 Major Targets For Anti-sars-cov2 Agentsmentioning

confidence: 99%

“…According to more recent studies, glycopeptide antibiotics, teicoplanin and eremomycin inhibit protein kinases, a key regulator of cell signaling. 59 Replacing the sugar moiety with hydrophobic residue in to aglycons and pseudo aglycons of glycopeptides is a means to synthesize glycopeptide aglycon derivatives with efficient activity against PKs of the viruses. 37 Another in vitro study also confirmed that various hydrophobic residues of teicoplanin aglycon carboxamides which were effective against PKs of SARS-COV, successfully inhibited all tested human PKs at low micromolar IC 50 values.…”

Section: Glycopeptides (Gps) As Potential Drugs For Coronavirus Treatmentioning

confidence: 99%

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<p>Glycopeptides as Potential Interventions for COVID-19</p>

Demsie¹,

Gebre²,

Yimer³

et al. 2020

BTT

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Coronavirus disease 2019 (COVID-19), an infectious disease that primarily attacks the human pulmonary system, is caused by a viral strain called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The outbreak emerged from Wuhan, China, and later spread throughout the world. Until the first week of May 2020, over 3.7 million cases had been reported worldwide and more than 258,000 had died due to the disease. So far, off label use of various drugs has been tried in many clinical settings, however, at present, there is no vaccine or antiviral treatment for human and animal coronaviruses. Therefore, repurposing of the available drugs may be promising to control emerging infections of SARS-COV2; however, new interventions are likely to require months to years to develop. Glycopeptides, which are active against gram-positive bacteria, have demonstrated significant activity against viral infections including SARS-COV and MERS-COV and have a high resemblance of sequence homology with SARS-COV2. Recent in vitro studies have also shown promising activities of aglycon derivative of glycopeptides and teicoplanin against SARS-COV2. Hydrophobic aglycon derivatives and teicoplanin, with minimal toxicity to human cell lines, inhibit entry and replication of SARS-COV2. These drugs block proteolysis of polyprotein a/b with replicase and transcription domains. Teicoplanin use was associated with complete viral clearance in a cohort of patients with severe COVID-19 symptoms. This review attempts to describe the activity, elucidate the possible mechanisms and potential clinical applications of existing glycopeptides against corona viruses, specifically SARS-COV2.

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Main trends in the design of semi-synthetic antibiotics of a new generation

Olsufyeva¹,

Yankovskaya²

2020

Russ. Chem. Rev.

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This review summarizes main advances achieved by Russian researchers in the synthesis and characterization of semi-synthetic antibiotics of a new generation in the period from 2004 to 2019. The following classes of compounds are considered as the basis for modification: polycyclic antibacterial glycopeptides of the vancomycin group, classical macrolides, antifungal polyene macrolides, the antitumour antibiotic olivomycin A, antitumour anthracyclines and broad-spectrum antibiotics, in particular, oligomycin A, heliomycin and some other. Main trends in the design of modern anti-infective and antitumour agents over this period are considered in relation to original natural antibiotics, which have been independently discovered by Russian researchers. It is shown that a new type of hybrid structures can, in principle, be synthesized based on glycopeptides, macrolides and other antibiotics, including heterodimers containing a new benzoxaborole pharmacophore. The review addresses the influence of the length of the spacer between two antibiotic molecules on the biological activity of hybrid structures. A combination of genetic engineering techniques and methods of organic synthesis is shown to be useful for the design of new potent antifungal antibiotics based on polyenes of the amphotericin B group. Many new semi-synthetic analogues exhibit important biological properties, such as a broad spectrum of activity and low toxicity. Emphasis is given to certain aspects related to investigation of a broad range of biological activity and mechanisms of action of new derivatives. The bibliography includes 101 references.

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Hydrophobic Derivatives of Glycopeptide Antibiotics as Inhibitors of Protein Kinases

Cited by 3 publications

References 29 publications

Emerging Roles of Glycopeptide Antibiotics: Moving beyond Gram-Positive Bacteria

Emerging Roles of Glycopeptide Antibiotics: Moving beyond Gram-Positive Bacteria

<p>Glycopeptides as Potential Interventions for COVID-19</p>

Main trends in the design of semi-synthetic antibiotics of a new generation

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