Antiviral Agents in Development for Zika Virus Infections
Identifieur interne : 000745 ( Ncbi/Merge ); précédent : 000744; suivant : 000746Antiviral Agents in Development for Zika Virus Infections
Auteurs : Mariana Baz ; Guy BoivinSource :
- Pharmaceuticals [ 1424-8247 ] ; 2019.
Abstract
In 1947, Zika virus (ZIKV), a mosquito-borne flavivirus was identified in Uganda and subsequently spread to Asia and the Pacific regions. In 2015, it was introduced in Brazil causing an important social and sanitary alarm due to its increased virulence and rapid dissemination. Importantly, ZIKV infections have been associated with severe neurological complications such as Guillain–Barré syndrome and microcephaly in fetuses and newborns. Although enormous efforts were made by investigators in the development of effective countermeasures against ZIKV, there is still no approved specific antiviral drug for the treatment of ZIKV infections. Herein, we review several anti ZIKV candidates including drugs targeting both the virus (structural proteins and enzymes) and cellular elements.
Url:
DOI: 10.3390/ph12030101
PubMed: 31261947
PubMed Central: 6789597
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Antiviral Agents in Development for Zika Virus Infections</title><author><name sortKey="Baz, Mariana" sort="Baz, Mariana" uniqKey="Baz M" first="Mariana" last="Baz">Mariana Baz</name></author><author><name sortKey="Boivin, Guy" sort="Boivin, Guy" uniqKey="Boivin G" first="Guy" last="Boivin">Guy Boivin</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31261947</idno><idno type="pmc">6789597</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789597</idno><idno type="RBID">PMC:6789597</idno><idno type="doi">10.3390/ph12030101</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000A93</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A93</idno><idno type="wicri:Area/Pmc/Curation">000A93</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000A93</idno><idno type="wicri:Area/Pmc/Checkpoint">000A00</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000A00</idno><idno type="wicri:Area/Ncbi/Merge">000745</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Antiviral Agents in Development for Zika Virus Infections</title><author><name sortKey="Baz, Mariana" sort="Baz, Mariana" uniqKey="Baz M" first="Mariana" last="Baz">Mariana Baz</name></author><author><name sortKey="Boivin, Guy" sort="Boivin, Guy" uniqKey="Boivin G" first="Guy" last="Boivin">Guy Boivin</name></author></analytic><series><title level="j">Pharmaceuticals</title><idno type="eISSN">1424-8247</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>In 1947, Zika virus (ZIKV), a mosquito-borne flavivirus was identified in Uganda and subsequently spread to Asia and the Pacific regions. In 2015, it was introduced in Brazil causing an important social and sanitary alarm due to its increased virulence and rapid dissemination. Importantly, ZIKV infections have been associated with severe neurological complications such as Guillain–Barré syndrome and microcephaly in fetuses and newborns. Although enormous efforts were made by investigators in the development of effective countermeasures against ZIKV, there is still no approved specific antiviral drug for the treatment of ZIKV infections. Herein, we review several anti ZIKV candidates including drugs targeting both the virus (structural proteins and enzymes) and cellular elements.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Kuno, G" uniqKey="Kuno G">G. Kuno</name></author><author><name sortKey="Chang, G J" uniqKey="Chang G">G.J. Chang</name></author><author><name sortKey="Tsuchiya, K R" uniqKey="Tsuchiya K">K.R. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Pharmaceuticals (Basel)</journal-id><journal-id journal-id-type="iso-abbrev">Pharmaceuticals (Basel)</journal-id><journal-id journal-id-type="publisher-id">pharmaceuticals</journal-id><journal-title-group><journal-title>Pharmaceuticals</journal-title></journal-title-group><issn pub-type="epub">1424-8247</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31261947</article-id><article-id pub-id-type="pmc">6789597</article-id><article-id pub-id-type="doi">10.3390/ph12030101</article-id><article-id pub-id-type="publisher-id">pharmaceuticals-12-00101</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Antiviral Agents in Development for Zika Virus Infections</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Baz</surname><given-names>Mariana</given-names></name><xref rid="c1-pharmaceuticals-12-00101" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Boivin</surname><given-names>Guy</given-names></name><xref rid="c1-pharmaceuticals-12-00101" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-pharmaceuticals-12-00101">Research Center in Infectious Diseases of the CHU of Québec and Université Laval, Québec City, QC G1V 4G2, Canada</aff><author-notes><corresp id="c1-pharmaceuticals-12-00101"><label>*</label>Correspondence: <email>Mariana.Baz@crchudequebec.ulaval.ca</email> (M.B.); <email>Guy.Boivin@crchul.ulaval.ca</email> (G.B.); Tel.: +1-418-525-4444 (ext. 48281) (M.B.); +1-418-654-2705 (G.B.)</corresp></author-notes><pub-date pub-type="epub"><day>29</day><month>6</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>9</month><year>2019</year></pub-date><volume>12</volume><issue>3</issue><elocation-id>101</elocation-id><history><date date-type="received"><day>31</day><month>5</month><year>2019</year></date><date date-type="accepted"><day>26</day><month>6</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>In 1947, Zika virus (ZIKV), a mosquito-borne flavivirus was identified in Uganda and subsequently spread to Asia and the Pacific regions. In 2015, it was introduced in Brazil causing an important social and sanitary alarm due to its increased virulence and rapid dissemination. Importantly, ZIKV infections have been associated with severe neurological complications such as Guillain–Barré syndrome and microcephaly in fetuses and newborns. Although enormous efforts were made by investigators in the development of effective countermeasures against ZIKV, there is still no approved specific antiviral drug for the treatment of ZIKV infections. Herein, we review several anti ZIKV candidates including drugs targeting both the virus (structural proteins and enzymes) and cellular elements.</p></abstract><kwd-group><kwd>Zika virus</kwd><kwd>antiviral agents</kwd><kwd>small molecules</kwd><kwd>virus targets</kwd><kwd>host targets</kwd><kwd>repurposing</kwd><kwd>pre-clinical studies</kwd></kwd-group></article-meta></front><floats-group><fig id="pharmaceuticals-12-00101-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Detailed structure of Zika virus (ZIKV) genome. ZIKV genomic RNA is capped but lacks poly A tail. The viral RNA codes for a polyprotein that is co-translationally cleaved to yield 11 proteins: three structural proteins (C prM/M and E) and eight non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, 2K, NS4B, and NS5).</p></caption><graphic xlink:href="pharmaceuticals-12-00101-g001"></graphic></fig><fig id="pharmaceuticals-12-00101-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Zika virus life cycle. ZIKV, an enveloped RNA virus, enters cells by receptor-mediated endocytosis and fuses its membranes by an acidic-pH-triggered mechanism in the endosome (via cell surface receptors such as AXL, Tyro3, DC-SIGN and TIM-1) to release the viral RNA. The ssRNA is then translated, and the resulting polyprotein is further cleaved into various structural and non-structural proteins (C, prM, E and NS proteins). Replication takes place in the endoplasmic reticulum (ER) surface. Transcription and replication of the dsDNA results in the formation of new viral mRNA and ssRNA, respectively. Virus assembly takes place in the ER membrane and leads to the formation of immature virions, which are transported through the exocytic pathway. The prM protein is cleaved and the virus is rendered mature. Finally, the mature virus exits the cell via exocytosis.</p></caption><graphic xlink:href="pharmaceuticals-12-00101-g002"></graphic></fig><table-wrap id="pharmaceuticals-12-00101-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">pharmaceuticals-12-00101-t001_Table 1</object-id><label>Table 1</label><caption><p>The table shows the structural and nonstructural ZIKV proteins from the 5’ to the 3’ untranslated regions. The name, size in amino acids, and function are shown for each protein.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Name</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Amino Acid Residues</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Function</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">C</td><td align="center" valign="middle" rowspan="1" colspan="1">122</td><td align="center" valign="middle" rowspan="1" colspan="1">Generation of nucleocapsid (encapsulates genomic RNA)</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">prM</td><td align="center" valign="middle" rowspan="1" colspan="1">168</td><td align="center" valign="middle" rowspan="1" colspan="1">Protects E protein during assembly</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">E</td><td align="center" valign="middle" rowspan="1" colspan="1">500</td><td align="center" valign="middle" rowspan="1" colspan="1">Envelope glycoprotein (membrane binding and fusion)</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">NS1</td><td align="center" valign="middle" rowspan="1" colspan="1">352</td><td align="center" valign="middle" rowspan="1" colspan="1">Replication and immune response regulation</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">NS2A</td><td align="center" valign="middle" rowspan="1" colspan="1">226</td><td align="center" valign="middle" rowspan="1" colspan="1">Replication and capsid assembly</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">NS2B</td><td align="center" valign="middle" rowspan="1" colspan="1">130</td><td align="center" valign="middle" rowspan="1" colspan="1">NS3 cofactor</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">NS3</td><td align="center" valign="middle" rowspan="1" colspan="1">617</td><td align="center" valign="middle" rowspan="1" colspan="1">Serine protease NTPase, RNA helicase</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">NS4A</td><td align="center" valign="middle" rowspan="1" colspan="1">127</td><td align="center" valign="middle" rowspan="1" colspan="1">Viral membrane formation</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">2K</td><td align="center" valign="middle" rowspan="1" colspan="1">23</td><td align="center" valign="middle" rowspan="1" colspan="1">Signal peptide</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">NS4B</td><td align="center" valign="middle" rowspan="1" colspan="1">251</td><td align="center" valign="middle" rowspan="1" colspan="1">Inhibits antiviral state</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NS5</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">903</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">RNA dependent RNA polymerase</td></tr></tbody></table></table-wrap><table-wrap id="pharmaceuticals-12-00101-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">pharmaceuticals-12-00101-t002_Table 2</object-id><label>Table 2</label><caption><p>Summary of the different antiviral options described in this manuscript.</p></caption><table frame="hsides" rules="groups"><tbody><tr><td colspan="4" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1"><bold>Direct-Acting Antivirals</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Name</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Mode of action</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>In vitro</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>In vivo</bold></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">7-deaza-2-CMA</td><td align="center" valign="middle" rowspan="1" colspan="1">RdRp inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">2-CMA, 2-CMC, 2-CMG, 2-CMU</td><td align="center" valign="middle" rowspan="1" colspan="1">RdRp inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Favipiravir</td><td align="center" valign="middle" rowspan="1" colspan="1">RdRp inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">NITD008</td><td align="center" valign="middle" rowspan="1" colspan="1">Pyrimidine synthesis inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Sofosbuvir</td><td align="center" valign="middle" rowspan="1" colspan="1">RdRp inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">BCX4430 *</td><td align="center" valign="middle" rowspan="1" colspan="1">RdRp inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Sinefungin</td><td align="center" valign="middle" rowspan="1" colspan="1">Pan-methyltransferase inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Myricetin, quercetin, luteolin, isorhamnetin, apigenin, curcumin</td><td align="center" valign="middle" rowspan="1" colspan="1">NS2B-NS3 protease inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Niclosamide, and nitazoxanide</td><td align="center" valign="middle" rowspan="1" colspan="1">NS2B-NS3 protease inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Temoporfin</td><td align="center" valign="middle" rowspan="1" colspan="1">NS2B-NS3 protease inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Novobiocin</td><td align="center" valign="middle" rowspan="1" colspan="1">NS2B-NS3 protease inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Suramin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NS3 inhibitor</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">√</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">X</td></tr><tr><td colspan="4" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Host-Targeting Antivirals</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Name</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Mode of action</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>In vitro</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>In vivo</bold></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Ribavirin</td><td align="center" valign="middle" rowspan="1" colspan="1">Several mechanisms including purine synthesis inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Merimepodib and mycophenolic acid</td><td align="center" valign="middle" rowspan="1" colspan="1">Inosine monophosphate dehydrogenase (IMPDH) inhibitors</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Azathioprine</td><td align="center" valign="middle" rowspan="1" colspan="1">Purine synthesis inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">6-azauridine, 5-fluorouracil</td><td align="center" valign="middle" rowspan="1" colspan="1">Pirimidine synthesis inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">lovastatin</td><td align="center" valign="middle" rowspan="1" colspan="1">HMG-CoA reductase inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Azithromycin</td><td align="center" valign="middle" rowspan="1" colspan="1">Unknown mechanisms of action against ZIKV</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" rowspan="1" colspan="1">Inhibition of pH-dependent steps of viral replication</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Saliphenylhalamide</td><td align="center" valign="middle" rowspan="1" colspan="1">Viral entry inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Obatoclax mesylate (GX15-070)</td><td align="center" valign="middle" rowspan="1" colspan="1">Bcl-2 protein inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">PHA-690509</td><td align="center" valign="middle" rowspan="1" colspan="1">Cyclin-dependent kinase inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">MK-801, agmatine, and ifenprodil</td><td align="center" valign="middle" rowspan="1" colspan="1">Neuronal cell death inhibitor</td><td align="center" valign="middle" rowspan="1" colspan="1">√</td><td align="center" valign="middle" rowspan="1" colspan="1">X</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Memantine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Neuronal cell death inhibitor</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">√</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">√</td></tr></tbody></table><table-wrap-foot><fn><p>* Denotes drugs under clinical trials, X: not done. HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list></list><tree><noCountry><name sortKey="Baz, Mariana" sort="Baz, Mariana" uniqKey="Baz M" first="Mariana" last="Baz">Mariana Baz</name><name sortKey="Boivin, Guy" sort="Boivin, Guy" uniqKey="Boivin G" first="Guy" last="Boivin">Guy Boivin</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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