Synthesis of Antiviral Perfluoroalkyl Derivatives of Teicoplanin and Vancomycin

Bereczki, Ilona; Csávás, Magdolna; Szűcs, Zsolt; Rőth, Erzsébet; Batta, Gyula; Ostorházi, Eszter; Naesens, Lieve; Borbás, Anikó; Herczegh, Pál

doi:10.1002/cmdc.202000260

Cited by 13 publications

(26 citation statements)

References 46 publications

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“…The authors concluded that the anti-SARS-CoV-2 activity of teicoplanin could be more effective at early infections, which is in accordance with recent results by Zhao et al [20]. We, and others, have demonstrated that the antiviral spectrum and efficacy of g peptide antibiotics can be increased by lipophilic modifications, and a number of isynthetic lipophilic derivatives of the antibiotics vancomycin, teicoplanin and rist have been published that showed good antiviral activity against coronaviruses [25-2 well as HIV [28], flaviviruses [29] and influenza viruses [26,27,[30][31][32][33][34]. Unfortunatel high antiviral activity is often associated with cytotoxicity [33,34].…”

Section: Introductionsupporting

confidence: 89%

“…Carotenoids are natural hydrophobic products with 40 carbon atoms, having c gated polyenic structures and possessing a number of beneficial biological activiti cluding antioxidant and immune enhancer properties, the regression of malignant le and mutagenesis inhibition [35][36][37]. Carotenoids are susceptible to oxidation; the We, and others, have demonstrated that the antiviral spectrum and efficacy of glycopeptide antibiotics can be increased by lipophilic modifications, and a number of semisynthetic lipophilic derivatives of the antibiotics vancomycin, teicoplanin and ristocetin have been published that showed good antiviral activity against coronaviruses [25][26][27], as well as HIV [28], flaviviruses [29] and influenza viruses [26,27,[30][31][32][33][34]. Unfortunately, the high antiviral activity is often associated with cytotoxicity [33,34].…”

Section: Introductionmentioning

confidence: 99%

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Natural Apocarotenoids and Their Synthetic Glycopeptide Conjugates Inhibit SARS-CoV-2 Replication

et al. 2021

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The protracted global COVID-19 pandemic urges the development of new drugs against the causative agent SARS-CoV-2. The clinically used glycopeptide antibiotic, teicoplanin, emerged as a potential antiviral, and its efficacy was improved with lipophilic modifications. This prompted us to prepare new lipophilic apocarotenoid conjugates of teicoplanin, its pseudoaglycone and the related ristocetin aglycone. Their antiviral effect was tested against SARS-CoV-2 in Vero E6 cells, using a cell viability assay and quantitative PCR of the viral RNA, confirming their micromolar inhibitory activity against viral replication. Interestingly, two of the parent apocarotenoids, bixin and β-apo-8′carotenoic acid, exerted remarkable anti-SARS-CoV-2 activity. Mechanistic studies involved cathepsin L and B, as well as the main protease 3CLPro, and the results were rationalized by computational studies. Glycopeptide conjugates show dual inhibitory action, while apocarotenoids have mostly cathepsin B and L affinity. Since teicoplanin is a marketed antibiotic and the natural bixin is an approved, cheap and widely used red colorant food additive, these readily available compounds and their conjugates as potential antivirals are worthy of further exploration.

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Section: Introductionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Natural Apocarotenoids and Their Synthetic Glycopeptide Conjugates Inhibit SARS-CoV-2 Replication

et al. 2021

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“…Teicoplanin is a glycopeptide antibiotic with its main activity to treat bacterial infection (Reynolds, 1989;Zhou et al, 2016). In vitro experiments demonstrated that this drug inhibited cell entry of the EBOV into primary human umbilical vein endothelial cells, A549 cells, HeLa cells, and THP-1 cells with an IC50 of 0.34 μM (Zhou et al, 2016), as well as its derivatives demonstrated antiviral activity against influenza strains, vaccinia, herpes, and human coronavirus (Bereczki et al, 2020). Recently, it was published that teicoplanin potently blocks the HIV-luc/ 2019-nCoV-S pseudoviruses entry into human A549 cells with a IC50 of 1.66 μM, suggesting this could be caused by the cathepsin L inhibition.…”

Section: Discussionmentioning

confidence: 99%

Repurposing Approved Drugs for Guiding COVID-19 Prophylaxis: A Systematic Review

et al. 2020

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The SARS-CoV-2 outbreak originally appeared in China in December 2019 and became a global pandemic in March 2020. This infectious disease has directly affected public health and the world economy. Several palliative therapeutic treatments and prophylaxis strategies have been used to control the progress of this viral infection, including pre-(PrEP) and post-exposure prophylaxis. On the other hand, research groups around the world are still studying novel drug prophylaxis and treatment using repurposing approaches, as well as vaccination options, which are in different pre-clinical and clinical testing phases. This systematic review evaluated 1,228 articles from the PubMed and Scopus indexing databases, following the Kitchenham bibliographic searching protocol, with the aim to list drug candidates, potentially approved to be used as new options for SARS-CoV-2 prophylaxis clinical trials and medical protocols. In searching protocol, we used the following keywords: “Covid-19 or SARS-CoV-2” or “Coronavirus or 2019 nCoV,” “prophylaxis,” “prophylactic,” “pre-exposure,” “COVID-19 or SARS-CoV-2 Chemoprophylaxis,” “repurposed,” “strategies,” “clinical,” “trials,” “anti-SARS-CoV-2,” “anti-covid-19,” “Antiviral,” “Therapy prevention in vitro,” in cells “and” human testing. After all protocol steps, we selected 60 articles that included: 15 studies with clinical data, 22 studies that used in vitro experiments, seven studies using animal models, and 18 studies performed with in silico experiments. Additionally, we included more 22 compounds between FDA approved drugs and drug-like like molecules, which were tested in large-scale screenings, as well as those repurposed approved drugs with new mechanism of actions. The drugs selected in this review can assist clinical studies and medical guidelines on the rational repurposing of known antiviral drugs for COVID-19 prophylaxis.

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“…Moreover, the light-promoted radical addition reaction [25] of commercially available perfluoroalkyl iodides onto the C19-C20 double bond allows the introduction of fluorous side chains into the pleuromutilin skeleton. Importantly, perfluoroalkylated derivatives of teicoplanin and vancomycin have recently been synthesized [26] by our group, and the introduced perfluorous side chains having a dual hydrophobic and lipophobic character [27] have remarkably improved the antimicrobial properties of the parent glycopeptide antibiotics.…”

Section: General Methodsmentioning

confidence: 99%

The Very First Modification of Pleuromutilin and Lefamulin by Photoinitiated Radical Addition Reactions—Synthesis and Antibacterial Studies

Páll

Rőth

et al. 2021

Pharmaceutics

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Pleuromutilin is a fungal diterpene natural product with antimicrobial properties, semisynthetic derivatives of which are used in veterinary and human medicine. The development of bacterial resistance to pleuromutilins is known to be very slow, which makes the tricyclic diterpene skeleton of pleuromutilin a very attractive starting structure for the development of new antibiotic derivatives that are unlikely to induce resistance. Here, we report the very first synthetic modifications of pleuromutilin and lefamulin at alkene position C19–C20, by two different photoinduced addition reactions, the radical thiol-ene coupling reaction, and the atom transfer radical additions (ATRAs) of perfluoroalkyl iodides. Pleuromutilin were modified with the addition of several alkyl- and aryl-thiols, thiol-containing amino acids and nucleoside and carbohydrate thiols, as well as perfluoroalkylated side chains. The antibacterial properties of the novel semisynthetic pleuromutilin derivatives were investigated on a panel of bacterial strains, including susceptible and multiresistant pathogens and normal flora members. We have identified some novel semisynthetic pleuromutilin and lefamulin derivatives with promising antimicrobial properties.

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Synthesis of Antiviral Perfluoroalkyl Derivatives of Teicoplanin and Vancomycin

Cited by 13 publications

References 46 publications

Natural Apocarotenoids and Their Synthetic Glycopeptide Conjugates Inhibit SARS-CoV-2 Replication

Natural Apocarotenoids and Their Synthetic Glycopeptide Conjugates Inhibit SARS-CoV-2 Replication

Repurposing Approved Drugs for Guiding COVID-19 Prophylaxis: A Systematic Review

The Very First Modification of Pleuromutilin and Lefamulin by Photoinitiated Radical Addition Reactions—Synthesis and Antibacterial Studies

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