![]() ![]() However, to date, the rarely used and mildly effective Ribavirin (RBV) is the only BSAA approved for the treatment of infections caused by different virus families. Therefore, development of pan-viral drugs (broad-spectrum antiviral agents BSAAs) capable of inhibiting the replication of multiple viruses belonging to different families, is an ambitious but attractive option in preparedness for outbreaks of previously unknown viral diseases and also for the treatment of widespread viral infections where an effective drug is not available yet. These diagnostic and therapeutic issues are even more serious in the case of newly emerging potentially pandemic viruses or in case of emerging variants with higher mortality rate since the time needed to develop a specific vaccine or drug is not compatible with a prompt response. DENV/SARS-CoV-2 or DENV/influenza ), which creates immune response disorders, confusion in diagnosis and delays in treatment, leading to additive or synergistic morbidities. DENV/ZIKV ), but also by different virus families (e.g. ![]() An additional problem with flavivirus infections is represented by coinfections, not only by different viruses in the same family (e.g. The epidemic potential of these flaviviruses is well represented by the increasing number of autochthonous vector-borne flavivirus infections in the last decade. The National Institute of Allergy and Infectious Diseases (NIAID) has therefore classified Dengue virus (DENV), West Nile virus (WNV), and ZIKV as categories A and B emerging infectious pathogens, accounting for 17% of infections worldwide and for which no drugs or universally protective vaccines are currently available. As an example, a single casual mutation (S139 N) in ZIKV has been recently linked to an increased infectivity in vitro, to more severe microcephaly and higher mortality rates in neonatal mice. In fact, viruses are subject to continuous evolution and new variants may become more virulent and/or acquire different tissue tropism, as recently documented for Zika virus (ZIKV) isolates causing microcephaly and other congenital anomalies in fetus as well as neurologic disorders in adults. Flaviviruses) may also represent a serious epidemic threat. The ongoing severe coronavirus disease 2019 (COVID-19) pandemic caused by the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is just one of the possible outcome, but emerging widespread viruses with moderate mortality rate (e.g. As human activity takes people into new environments or down to anti-scientific pathways, the risk of zoonotic virus spillover into humans increases and, along with that, the possibility of new epidemic outbreaks in the coming decades. In addition, old viruses previously confined in specific and isolated areas are re-emerging and rapidly spreading as a consequence of globalization and climate changes, but also those viruses that were thought to be eradicated with vaccination campaigns are reappearing due to public misinformation, no-vax campaigns and geopolitical instability in specific territories. In 2018, the Global Virome Project estimated that our planet harbours around 1.6 million yet-to-be-discovered potentially zoonotic viruses, and less than 1% of these has been identified to date. ![]() Despite much social visibility and alertness to the potential impact of widespread epidemics of devastating viral infections, a significant number of viral pathogens remains without effective treatment or cure, whilst only a few major viral infections (except HIV) can be prevented with vaccines. Viruses make up roughly two-thirds of all newly discovered human pathogens - far more than either bacteria or fungi. The multi-target effect of 6i on flavivirus replication was also analyzed in whole cell studies ( in vitro selection and immunofluorescence) and against isolated host/viral targets. Interestingly, 6i also inhibited SARS-CoV-2 replication in different cell lines, with higher potency on Calu-3 cells that better mimic the SARS-CoV-2 infection in vivo (IC 50 = 0.5 μM, SI = 240). Among the synthesized compounds, 6i showed low micromolar potency against Dengue, Zika, West Nile and Influenza A viruses (IC 50 = 0.5–5.3 μM) with high selectivity index. Starting from previously identified anti-flavivirus hits, we report herein the identification of promising BSAAs by submitting the multi-target 2,6-diaminopurine chemotype to a system-oriented optimization based on phenotypic screening on cell cultures infected with different viruses. Broad-spectrum antiviral agents (BSAAs) represent the ideal option for a prompt response against multiple viruses, new and re-emerging. The worldwide circulation of different viruses coupled with the increased frequency and diversity of new outbreaks, strongly highlight the need for new antiviral drugs to quickly react against potential pandemic pathogens. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |