Abstract:Gemcitabine is a
nucleoside analogue of deoxycytidine and has been
reported to be a broad-spectrum antiviral agent against both DNA and
RNA viruses. Screening of a nucleos(t)ide analogue-focused library
identified gemcitabine and its derivatives (compounds 1, 2a, and 3a) blocking influenza virus
infection. To improve their antiviral selectivity by reducing cytotoxicity,
14 additional derivatives were synthesized in which the pyridine rings
of 2a and 3a were chemically modified. Structure-and-activity
and struc… Show more
“…Influenza virus [270] In human cells (HeLa), the compound was evaluated for its antiviral activity (EC 90 = 11.4-15.9 µM), more precisely the polymerase activity of influenza A virus PR8. To assess this, a negative-sense EGFP gene, flanked with 5 and 3 UTRs derived from the NS segment, was cloned under the control of the human RNA polymerase I promoter.…”
Section: Anti-yellow Fever Agentmentioning
confidence: 99%
“…Influenza virus [269] Through intervention in these host-virus interactions, the substituted furan-succinimide derivative can successfully impede viral replication and restrict the advancement of the infection, with the EC50 value determined to be 50 pM [270].…”
Antiviral properties of different oxa- and aza-heterocycles are identified and properly correlated with their structural features and discussed in this review article. The primary objective is to explore the activity of such ring systems as antiviral agents, as well as their synthetic routes and biological significance. Eventually, the structure–activity relationship (SAR) of the heterocyclic compounds, along with their salient characteristics are exhibited to build a suitable platform for medicinal chemists and biotechnologists. The synergistic conclusions are extremely important for the introduction of a newer tool for the future drug discovery program.
“…Influenza virus [270] In human cells (HeLa), the compound was evaluated for its antiviral activity (EC 90 = 11.4-15.9 µM), more precisely the polymerase activity of influenza A virus PR8. To assess this, a negative-sense EGFP gene, flanked with 5 and 3 UTRs derived from the NS segment, was cloned under the control of the human RNA polymerase I promoter.…”
Section: Anti-yellow Fever Agentmentioning
confidence: 99%
“…Influenza virus [269] Through intervention in these host-virus interactions, the substituted furan-succinimide derivative can successfully impede viral replication and restrict the advancement of the infection, with the EC50 value determined to be 50 pM [270].…”
Antiviral properties of different oxa- and aza-heterocycles are identified and properly correlated with their structural features and discussed in this review article. The primary objective is to explore the activity of such ring systems as antiviral agents, as well as their synthetic routes and biological significance. Eventually, the structure–activity relationship (SAR) of the heterocyclic compounds, along with their salient characteristics are exhibited to build a suitable platform for medicinal chemists and biotechnologists. The synergistic conclusions are extremely important for the introduction of a newer tool for the future drug discovery program.
Cell culture-based screening of a chemical library identified diphenoxylate as an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The observed 50% effective concentrations ranged between 1.4 and 4.9 µM against the original wild-type strain and its variants. Time-of-addition experiments indicated that diphenoxylate is an entry blocker targeting a host factor involved in viral infection. Fluorescence microscopic analysis visualized that diphenoxylate prevented SARS-CoV-2 particles from penetrating the cell membrane and also impaired endo-lysosomal acidification. Diphenoxylate exhibited a synergistic inhibitory effect on SARS-CoV-2 infection in human lung epithelial Calu-3 cells when combined with a transmembrane serine protease 2 (TMPRSS2) inhibitor, nafamostat. This synergy suggested that efficient antiviral activity is achieved by blocking both TMPRSS2-mediated early and endosome-mediated late SARS-CoV-2 entry pathways. The antiviral efficacy of diphenoxylate against SARS-CoV-2 was reproducible in a human tonsil organoids system. In a transgenic mouse model expressing the obligate SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, intranasal administration of diphenoxylate (10 mg/kg/day) significantly reduced the viral RNA copy number in the lungs by 70% on day 3. This study underscores that diphenoxylate represents a promising core scaffold, warranting further exploration for chemical modifications aimed at developing a new class of clinically effective antiviral drugs against SARS-CoV-2.
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