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1.
Biomed Pharmacother ; 158: 114213, 2023 Feb.
Article in English | MEDLINE | ID: covidwho-2232807

ABSTRACT

The rapid emergence of highly transmissible SARS-CoV-2 variants poses serious threat to the efficacy of vaccines and neutralizing antibodies. Thus, there is an urgent need to develop new and effective inhibitors against SARS-CoV-2 and future outbreaks. Here, we have identified a series of glycopeptide antibiotics teicoplanin derivatives that bind to the SARS-CoV-2 spike (S) protein, interrupt its interaction with ACE2 receptor and selectively inhibit viral entry mediated by S protein. Computation modeling predicts that these compounds interact with the residues in the receptor binding domain. More importantly, these teicoplanin derivatives inhibit the entry of both pseudotyped SARS-CoV-2 Delta and Omicron variants. Our study demonstrates the feasibility of developing small molecule entry inhibitors by targeting the interaction of viral S protein and ACE2. Together, considering the proven safety and pharmacokinetics of teicoplanin as a glycopeptide antibiotic, the teicoplanin derivatives hold great promise of being repurposed as pan-SARS-CoV-2 inhibitors.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/metabolism , Teicoplanin/pharmacology , Teicoplanin/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Virus Internalization , Spike Glycoprotein, Coronavirus/metabolism , Protein Binding , Anti-Bacterial Agents/pharmacology
2.
Sci Rep ; 12(1): 16001, 2022 09 26.
Article in English | MEDLINE | ID: covidwho-2042338

ABSTRACT

Patients infected with SARS-CoV-2 risk co-infection with Gram-positive bacteria, which severely affects their prognosis. Antimicrobial drugs with dual antiviral and antibacterial activity would be very useful in this setting. Although glycopeptide antibiotics are well-known as strong antibacterial drugs, some of them are also active against RNA viruses like SARS-CoV-2. It has been shown that the antiviral and antibacterial efficacy can be enhanced by synthetic modifications. We here report the synthesis and biological evaluation of seven derivatives of teicoplanin bearing hydrophobic or superbasic side chain. All but one teicoplanin derivatives were effective in inhibiting SARS-CoV-2 replication in VeroE6 cells. One lipophilic and three perfluoroalkyl conjugates showed activity against SARS-CoV-2 in human Calu-3 cells and against HCoV-229E, an endemic human coronavirus, in HEL cells. Pseudovirus entry and enzyme inhibition assays established that the teicoplanin derivatives efficiently prevent the cathepsin-mediated endosomal entry of SARS-CoV-2, with some compounds inhibiting also the TMPRSS2-mediated surface entry route. The teicoplanin derivatives showed good to excellent activity against Gram-positive bacteria resistant to all approved glycopeptide antibiotics, due to their ability to dually bind to the bacterial membrane and cell-wall. To conclude, we identified three perfluoralkyl and one monoguanidine analog of teicoplanin as dual inhibitors of Gram-positive bacteria and SARS-CoV-2.


Subject(s)
COVID-19 , Fluorocarbons , Anti-Bacterial Agents/chemistry , Antiviral Agents/chemistry , Cathepsins/pharmacology , Fluorocarbons/pharmacology , Glycopeptides/chemistry , Gram-Positive Bacteria , Humans , SARS-CoV-2 , Teicoplanin/pharmacology
3.
J Glob Antimicrob Resist ; 26: 308-316, 2021 09.
Article in English | MEDLINE | ID: covidwho-1313234

ABSTRACT

OBJECTIVES: The aim of this study was to investigate the trends in serotypes and in vitro antimicrobial susceptibility of Streptococcus pneumoniae causing adult invasive pneumococcal disease (IPD) to dalbavancin, telavancin, tedizolid, eravacycline, omadacycline and other comparator antibiotics from 2017-2020 following implementation of the 13-valent pneumococcal conjugate vaccine (PCV-13) and during the COVID-19 (coronavirus disease 2019) pandemic. METHODS: During the study period, 237 S. pneumoniae isolates were collected from non-duplicate patients, covering 15.0% of IPD cases in Taiwan. Antimicrobial susceptibility testing was performed using a Sensititre® system. A latex agglutination method (ImmuLex™ Pneumotest Kit) was used to determine serotypes. RESULTS: Susceptibility rates were high for vancomycin (100%), teicoplanin (100%) and linezolid (100%), followed by ceftaroline (non-meningitis) (98.3%), moxifloxacin (94.9%) and quinupristin/dalfopristin (89.9%). MIC50 and MIC90 values of dalbavancin, telavancin, tedizolid, eravacycline and omadacycline were generally low. Non-vaccine serotype 23A was the leading cause of IPD across the adult age range. Isolates of serotype 15B were slightly fewer than those of PCV-13 serotypes in patients aged ≥65 years. The overall case fatality rate was 15.2% (36/237) but was especially high for non-PCV-13 serotype 15B (21.4%; 3/14). Vaccine coverage was 44.7% for PCV-13 and 49.4% for the 23-valent pneumococcal polysaccharide vaccine (PPSV-23), but was 57% for both PCV-13 and PPSV-23. CONCLUSION: The incidence of IPD was stationary after PCV-13 introduction and only dramatically decreased in the COVID-19 pandemic in 2020. The MIC50 and MIC90 values of dalbavancin, telavancin, tedizolid, eravacycline, omadacycline were generally low for S. pneumoniae causing adult IPD.


Subject(s)
COVID-19 , Streptococcus pneumoniae , Adult , Aminoglycosides , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Drug Resistance, Bacterial , Humans , Lipoglycopeptides , Oxazolidinones , Pandemics , SARS-CoV-2 , Serogroup , Taiwan/epidemiology , Teicoplanin/analogs & derivatives , Teicoplanin/pharmacology , Tetracyclines , Tetrazoles
4.
Expert Rev Anti Infect Ther ; 19(9): 1125-1134, 2021 09.
Article in English | MEDLINE | ID: covidwho-1122062

ABSTRACT

INTRODUCTION: The COVID-19 pandemic has dramatically challenged the national health systems worldwide in the last months. Dalbavancin is a novel antibiotic with a long plasmatic half-life and simplified weekly administration regimens, thus representing a promising option for the outpatient treatment of Gram-positive infections and the early discharge of hospitalized patients. Dalbavancin is approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Many preliminary data seem to support its use in other indications, such as osteomyelitis, prosthetic joint infections, and infective endocarditis. AREAS COVERED: A search in the literature using validated keywords (dalbavancin, Gram-positive infections, Gram-positive cocci, ABSSSI, intravenous treatment, and long-acting antibiotics) was conducted on biomedical bibliographic databases (PubMed and Embase) from 2004 to 30 September 2020. Results were analyzed during two consensus conferences with the aim to review the current evidence on dalbavancin in Gram-positive infections, mainly ABSSSI, osteomyelitis, and infective endocarditis, highlight the main limitations of available studies and suggest possible advantages of the molecule. EXPERT OPINION: The board identifies some specific subgroups of patients with ABSSSIs who could mostly benefit from a treatment with dalbavancin and agrees that the design of homogenous and robust studies would allow a broader use of dalbavancin even in other clinical settings.


Subject(s)
COVID-19 , Gram-Positive Bacterial Infections/drug therapy , Teicoplanin/analogs & derivatives , Ambulatory Care/methods , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Drug Administration Schedule , Gram-Positive Bacterial Infections/microbiology , Humans , Skin Diseases, Bacterial/drug therapy , Skin Diseases, Bacterial/microbiology , Teicoplanin/administration & dosage , Teicoplanin/pharmacology
6.
Cell Res ; 31(1): 17-24, 2021 01.
Article in English | MEDLINE | ID: covidwho-953056

ABSTRACT

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8-10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Teicoplanin/analogs & derivatives , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Caco-2 Cells , Chlorocebus aethiops , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Protein Binding/drug effects , Teicoplanin/pharmacokinetics , Teicoplanin/pharmacology , Vero Cells
7.
Int J Biol Macromol ; 164: 2622-2631, 2020 Dec 01.
Article in English | MEDLINE | ID: covidwho-726538

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has emerged as a global catastrophe. The virus requires main protease for processing the viral polyproteins PP1A and PP1AB translated from the viral RNA. In search of a quick, safe and successful therapeutic agent; we screened various clinically approved drugs for the in-vitro inhibitory effect on 3CLPro which may be able to halt virus replication. The methods used includes protease activity assay, fluorescence quenching, surface plasmon resonance (SPR), Thermofluor® Assay, Size exclusion chromatography and in-silico docking studies. We found that Teicoplanin as most effective drug with IC50 ~ 1.5 µM. Additionally, through fluorescence quenching Stern-Volmer quenching constant (KSV) for Teicoplanin was estimated as 2.5 × 105 L·mol-1, which suggests a relatively high affinity between Teicoplanin and 3CLPro protease. The SPR shows good interaction between Teicoplanin and 3CLPro with KD ~ 1.6 µM. Our results provide critical insights into the mechanism of action of Teicoplanin as a potential therapeutic against COVID-19. We found that Teicoplanin is about 10-20 fold more potent in inhibiting protease activity than other drugs in use, such as lopinavir, hydroxychloroquine, chloroquine, azithromycin, atazanavir etc. Therefore, Teicoplanin emerged as the best inhibitor among all drug molecules we screened against 3CLPro of SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/enzymology , Drug Repositioning/methods , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Amino Acid Sequence , Antiviral Agents/chemistry , Betacoronavirus/physiology , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cysteine Endopeptidases , Drug Evaluation, Preclinical/methods , Humans , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protease Inhibitors/chemistry , SARS-CoV-2 , Teicoplanin/chemistry , Teicoplanin/pharmacology , Virus Replication/drug effects
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