Antiviral drug discovery: broad-spectrum drugs from nature

Martinez, Javier P; Sasse, Florenz; Brönstrup, Mark; Díez, Juana; Meyerhans, Andreas

doi:10.1039/c4np00085d

Cited by 159 publications

(129 citation statements)

References 284 publications

(485 reference statements)

Supporting

Mentioning

128

Contrasting

Unclassified

Order By: Relevance

“…In this regard, a novel antiviral approach (economical, simple to use, and environmental friendly) is the use of natural compounds (Martinez et al, 2015), such as the polyphenols present in plants and natural products, such as wine and tea (Hsu, 2015). Polyphenols constitute important metabolites of plants and are generally involved in defense against ultraviolet radiation or aggression by pathogens.…”

Section: Introductionmentioning

confidence: 99%

Antiviral Properties of the Natural Polyphenols Delphinidin and Epigallocatechin Gallate against the Flaviviruses West Nile Virus, Zika Virus, and Dengue Virus

et al. 2017

View full text Add to dashboard Cite

The Flavivirus genus contains important pathogens, such as West Nile virus (WNV), Zika virus (ZIKV), and Dengue virus (DENV), which are enveloped plus-strand RNA viruses transmitted by mosquitoes and constitute a worrisome threat to global human and animal health. Currently no licensed drugs against them are available, being, thus, still necessary the search for effective antiviral molecules. In this line, a novel antiviral approach (economical, simple to use, and environmental friendly) is the use of natural compounds. Consequently, we have tested the antiviral potential of different polyphenols present in plants and natural products, such as wine and tea, against WNV, ZIKV, and DENV. So that, we assayed the effect of a panel of structurally related polyphenols [delphinidin (D), cyanidin (Cy), catechin (C), epicatechin (EC), epigallocatechin (EGC), and epigallocatechin gallate (EGCG)] on WNV infection, and found that D and EGCG inhibited more effectively the virus production. Further analysis with both compounds indicated that they mainly affected the attachment and entry steps of the virus life cycle. Moreover, D and EGCG showed a direct effect on WNV particles exerting a virucidal effect. We showed a similar inhibition of viral production of these compounds on WNV variants that differed on acidic pH requirements for viral fusion, indicating that their antiviral activity against WNV is produced by a virucidal effect rather than by an inhibition of pH-dependent viral fusion. Both polyphenols also reduced the infectivity of ZIKV and DENV. Therefore, D and EGCG impair the infectivity in cell culture of these three medically relevant flaviviruses.

show abstract

Section: Introductionmentioning

confidence: 99%

Antiviral Properties of the Natural Polyphenols Delphinidin and Epigallocatechin Gallate against the Flaviviruses West Nile Virus, Zika Virus, and Dengue Virus

et al. 2017

View full text Add to dashboard Cite

show abstract

“…RNA viruses, in particular, have high mutation rates owing to their error-prone polymerases and rapidly generating drug-resistant variants (8)(9)(10). On this basis, blocking host cell factors required by different viruses for their replication might be a low cost and short time but effective route to develop broad spectrum antivirals able to limit the occurrence of drug resistance (11,12).…”

mentioning

confidence: 99%

Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

Brai

Fazi

Tintori

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

100

110

View full text Add to dashboard Cite

Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEADbox polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target.broad spectrum antivirals | DDX3 | host factors | resistance | coinfections

show abstract

“…One appealing strategy to avoid antiviral drug resistance is the targeting of virus-host interactions (2). Drugs that act by blocking specific host functions required by many different viruses have the additional potential to treat a wide range of viral infections and coinfections (broad-spectrum antivirals) (3). Inhibitors of the endoplasmic reticulum (ER) glycoprotein quality control (QC) machinery, used by most enveloped viruses for the correct folding of their surface glycoproteins (4), represent one class of promising host-targeting, broad-spectrum antivirals.…”

mentioning

confidence: 99%

Structures of mammalian ER α-glucosidase II capture the binding modes of broad-spectrum iminosugar antivirals

Caputo

Alonzi

Marti

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The biosynthesis of enveloped viruses depends heavily on the host cell endoplasmic reticulum (ER) glycoprotein quality control (QC) machinery. This dependency exceeds the dependency of host glycoproteins, offering a window for the targeting of ERQC for the development of broad-spectrum antivirals. We determined smallangle X-ray scattering (SAXS) and crystal structures of the main ERQC enzyme, ER α-glucosidase II (α-GluII; from mouse), alone and in complex with key ligands of its catalytic cycle and antiviral iminosugars, including two that are in clinical trials for the treatment of dengue fever. The SAXS data capture the enzyme's quaternary structure and suggest a conformational rearrangement is needed for the simultaneous binding of a monoglucosylated glycan to both subunits. The X-ray structures with key catalytic cycle intermediates highlight that an insertion between the +1 and +2 subsites contributes to the enzyme's activity and substrate specificity, and reveal that the presence of D-mannose at the +1 subsite renders the acid catalyst less efficient during the cleavage of the monoglucosylated substrate. The complexes with iminosugar antivirals suggest that inhibitors targeting a conserved ring of aromatic residues between the α-GluII +1 and +2 subsites would have increased potency and selectivity, thus providing a template for further rational drug design.broad-spectrum antiviral | ER α-glucosidase II | eukaryotic secretion | glycoprotein folding | iminosugar

show abstract

Antiviral drug discovery: broad-spectrum drugs from nature

Cited by 159 publications

References 284 publications

Antiviral Properties of the Natural Polyphenols Delphinidin and Epigallocatechin Gallate against the Flaviviruses West Nile Virus, Zika Virus, and Dengue Virus

Antiviral Properties of the Natural Polyphenols Delphinidin and Epigallocatechin Gallate against the Flaviviruses West Nile Virus, Zika Virus, and Dengue Virus

Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

Structures of mammalian ER α-glucosidase II capture the binding modes of broad-spectrum iminosugar antivirals

Contact Info

Product

Resources

About