Inhibition, escape, and attenuated growth of severe acute respiratory syndrome coronavirus treated with antisense morpholino oligomers
Identifieur interne : 004E03 ( Main/Exploration ); précédent : 004E02; suivant : 004E04Inhibition, escape, and attenuated growth of severe acute respiratory syndrome coronavirus treated with antisense morpholino oligomers
Auteurs : Benjamin W. Neuman [États-Unis] ; David A. Stein [États-Unis] ; Andrew D. Kroeker [États-Unis] ; Michael J. Churchill [États-Unis] ; Alice M. Kim [États-Unis] ; Peter Kuhn [États-Unis] ; Philip Dawson [États-Unis] ; Hong M. Moulton [États-Unis] ; Richard K. Bestwick [États-Unis] ; Patrick L. Iversen [États-Unis] ; Michael J. Buchmeier [États-Unis]Source :
- Journal of virology [ 0022-538X ] ; 2005.
Descripteurs français
- KwdFr :
- Animaux, Antiviraux (pharmacologie), Cellules Vero, Conception de médicament, Conformation d'acide nucléique, Données de séquences moléculaires, Effet cytopathogène viral, Morpholines (pharmacologie), Morpholinos, Mutation, Passage en série, Peptides, Régions 5' non traduites, Résistance virale aux médicaments, Syndrome respiratoire aigu sévère, Séquence nucléotidique, Transcription génétique (), Virus du SRAS (), Virus du SRAS (croissance et développement), Virus du SRAS (génétique).
- MESH :
- croissance et développement : Virus du SRAS.
- génétique : Virus du SRAS.
- pharmacologie : Antiviraux, Morpholines.
- Pascal (Inist)
- Animaux, Cellules Vero, Conception de médicament, Conformation d'acide nucléique, Coronavirus, Données de séquences moléculaires, Effet cytopathogène viral, Microbiologie, Morpholinos, Mutation, Passage en série, Peptides, Régions 5' non traduites, Résistance virale aux médicaments, Syndrome respiratoire aigu sévère, Séquence nucléotidique, Transcription génétique, Virologie, Syndrome respiratoire aigu sévère, Virus du SRAS.
English descriptors
- KwdEn :
- 5' Untranslated Regions, Animals, Antiviral Agents (pharmacology), Base Sequence, Chlorocebus aethiops, Coronavirus, Cytopathogenic Effect, Viral, Drug Design, Drug Resistance, Viral, Microbiology, Molecular Sequence Data, Morpholines (pharmacology), Morpholinos, Mutation, Nucleic Acid Conformation, Peptides, SARS Virus (drug effects), SARS Virus (genetics), SARS Virus (growth & development), Serial Passage, Severe Acute Respiratory Syndrome, Severe acute respiratory syndrome, Transcription, Genetic (drug effects), Vero Cells, Virology.
- MESH :
- chemical , pharmacology : Antiviral Agents, Morpholines.
- chemical : 5' Untranslated Regions, Morpholinos, Peptides.
- drug effects : SARS Virus, Transcription, Genetic.
- genetics : SARS Virus.
- growth & development : SARS Virus.
- Animals, Base Sequence, Chlorocebus aethiops, Cytopathogenic Effect, Viral, Drug Design, Drug Resistance, Viral, Molecular Sequence Data, Mutation, Nucleic Acid Conformation, Serial Passage, Severe Acute Respiratory Syndrome, Vero Cells.
Abstract
The recently emerged severe acute respiratory syndrome coronavirus (SARS-CoV) is a potent pathogen of humans and is capable of rapid global spread. Peptide-conjugated antisense morpholino oligomers (P-PMO) were designed to bind by base pairing to specific sequences in the SARS-CoV (Tor2 strain) genome. The P-PMO were tested for their capacity to inhibit production of infectious virus as well as to probe the function of conserved viral RNA motifs and secondary structures. Several virus-targeted P-PMO and a random-sequence control P-PMO showed low inhibitory activity against SARS coronavirus. Certain other virus-targeted P-PMO reduced virus-induced cytopathology and cell-to-cell spread as a consequence of decreasing viral amplification. Active P-PMO were effective when administered at any time prior to peak viral synthesis and exerted sustained antiviral effects while present in culture medium. P-PMO showed low nonspecific inhibitory activity against translation of nontargeted RNA or growth of the arenavirus lymphocytic choriomeningitis virus. Two P-PMO targeting the viral transcription-regulatory sequence (TRS) region in the 5' untranslated region were the most effective inhibitors tested. After several viral passages in the presence of a TRS-targeted P-PMO, partially drug-resistant SARS-CoV mutants arose which contained three contiguous base point mutations at the binding site of a TRS-targeted P-PMO. Those partially resistant viruses grew more slowly and formed smaller plaques than wild-type SARS-CoV. These results suggest PMO compounds have powerful therapeutic and investigative potential toward coronavirus infection.
Affiliations:
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Neuman</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>The Scripps Research Institute, Division of Virology, Department of Neuropharmacology, 10550 North Torrey Pines Rd</s1><s2>La Jolla, California 92037</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>La Jolla, California 92037</wicri:noRegion></affiliation></author><author><name sortKey="Stein, David A" sort="Stein, David A" uniqKey="Stein D" first="David A." last="Stein">David A. Stein</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>AVI BioPharma Inc., 4575 SW Research Way</s1><s2>Corvallis, Oregon 97333</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Corvallis, Oregon 97333</wicri:noRegion></affiliation></author><author><name sortKey="Kroeker, Andrew D" sort="Kroeker, Andrew D" uniqKey="Kroeker A" first="Andrew D." last="Kroeker">Andrew D. Kroeker</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>AVI BioPharma Inc., 4575 SW Research Way</s1><s2>Corvallis, Oregon 97333</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Corvallis, Oregon 97333</wicri:noRegion></affiliation></author><author><name sortKey="Churchill, Michael J" sort="Churchill, Michael J" uniqKey="Churchill M" first="Michael J." last="Churchill">Michael J. Churchill</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Cell Biology, 10550 North Torrey Pines Rd</s1><s2>La Jolla, California 92037</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>La Jolla, California 92037</wicri:noRegion></affiliation></author><author><name sortKey="Kim, Alice M" sort="Kim, Alice M" uniqKey="Kim A" first="Alice M." last="Kim">Alice M. Kim</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>The Scripps Research Institute, Division of Virology, Department of Neuropharmacology, 10550 North Torrey Pines Rd</s1><s2>La Jolla, California 92037</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>La Jolla, California 92037</wicri:noRegion></affiliation></author><author><name sortKey="Kuhn, Peter" sort="Kuhn, Peter" uniqKey="Kuhn P" first="Peter" last="Kuhn">Peter Kuhn</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Cell Biology, 10550 North Torrey Pines Rd</s1><s2>La Jolla, California 92037</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>La Jolla, California 92037</wicri:noRegion></affiliation></author><author><name sortKey="Dawson, Philip" sort="Dawson, Philip" uniqKey="Dawson P" first="Philip" last="Dawson">Philip Dawson</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Cell Biology, 10550 North Torrey Pines Rd</s1><s2>La Jolla, California 92037</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>La Jolla, California 92037</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Rd</s1><s2>La Jolla, California 92037</s2><s3>USA</s3><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>La Jolla, California 92037</wicri:noRegion></affiliation></author><author><name sortKey="Moulton, Hong M" sort="Moulton, Hong M" uniqKey="Moulton H" first="Hong M." last="Moulton">Hong M. Moulton</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>AVI BioPharma Inc., 4575 SW Research Way</s1><s2>Corvallis, Oregon 97333</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Corvallis, Oregon 97333</wicri:noRegion></affiliation></author><author><name sortKey="Bestwick, Richard K" sort="Bestwick, Richard K" uniqKey="Bestwick R" first="Richard K." last="Bestwick">Richard K. Bestwick</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>AVI BioPharma Inc., 4575 SW Research Way</s1><s2>Corvallis, Oregon 97333</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Corvallis, Oregon 97333</wicri:noRegion></affiliation></author><author><name sortKey="Iversen, Patrick L" sort="Iversen, Patrick L" uniqKey="Iversen P" first="Patrick L." last="Iversen">Patrick L. Iversen</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>AVI BioPharma Inc., 4575 SW Research Way</s1><s2>Corvallis, Oregon 97333</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Corvallis, Oregon 97333</wicri:noRegion></affiliation></author><author><name sortKey="Buchmeier, Michael J" sort="Buchmeier, Michael J" uniqKey="Buchmeier M" first="Michael J." last="Buchmeier">Michael J. Buchmeier</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>The Scripps Research Institute, Division of Virology, Department of Neuropharmacology, 10550 North Torrey Pines Rd</s1><s2>La Jolla, California 92037</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>La Jolla, California 92037</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Journal of virology</title><title level="j" type="abbreviated">J. virol.</title><idno type="ISSN">0022-538X</idno><imprint><date when="2005">2005</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of virology</title><title level="j" type="abbreviated">J. virol.</title><idno type="ISSN">0022-538X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>5' Untranslated Regions</term><term>Animals</term><term>Antiviral Agents (pharmacology)</term><term>Base Sequence</term><term>Chlorocebus aethiops</term><term>Coronavirus</term><term>Cytopathogenic Effect, Viral</term><term>Drug Design</term><term>Drug Resistance, Viral</term><term>Microbiology</term><term>Molecular Sequence Data</term><term>Morpholines (pharmacology)</term><term>Morpholinos</term><term>Mutation</term><term>Nucleic Acid Conformation</term><term>Peptides</term><term>SARS Virus (drug effects)</term><term>SARS Virus (genetics)</term><term>SARS Virus (growth & development)</term><term>Serial Passage</term><term>Severe Acute Respiratory Syndrome</term><term>Severe acute respiratory syndrome</term><term>Transcription, Genetic (drug effects)</term><term>Vero Cells</term><term>Virology</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antiviraux (pharmacologie)</term><term>Cellules Vero</term><term>Conception de médicament</term><term>Conformation d'acide nucléique</term><term>Données de séquences moléculaires</term><term>Effet cytopathogène viral</term><term>Morpholines (pharmacologie)</term><term>Morpholinos</term><term>Mutation</term><term>Passage en série</term><term>Peptides</term><term>Régions 5' non traduites</term><term>Résistance virale aux médicaments</term><term>Syndrome respiratoire aigu sévère</term><term>Séquence nucléotidique</term><term>Transcription génétique ()</term><term>Virus du SRAS ()</term><term>Virus du SRAS (croissance et développement)</term><term>Virus du SRAS (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Morpholines</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>5' Untranslated Regions</term><term>Morpholinos</term><term>Peptides</term></keywords><keywords scheme="MESH" qualifier="croissance et développement" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>SARS Virus</term><term>Transcription, Genetic</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="growth & development" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Morpholines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Base Sequence</term><term>Chlorocebus aethiops</term><term>Cytopathogenic Effect, Viral</term><term>Drug Design</term><term>Drug Resistance, Viral</term><term>Molecular Sequence Data</term><term>Mutation</term><term>Nucleic Acid Conformation</term><term>Serial Passage</term><term>Severe Acute Respiratory Syndrome</term><term>Vero Cells</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Animaux</term><term>Cellules Vero</term><term>Conception de médicament</term><term>Conformation d'acide nucléique</term><term>Coronavirus</term><term>Données de séquences moléculaires</term><term>Effet cytopathogène viral</term><term>Microbiologie</term><term>Morpholinos</term><term>Mutation</term><term>Passage en série</term><term>Peptides</term><term>Régions 5' non traduites</term><term>Résistance virale aux médicaments</term><term>Syndrome respiratoire aigu sévère</term><term>Séquence nucléotidique</term><term>Transcription génétique</term><term>Virologie</term><term>Syndrome respiratoire aigu sévère</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The recently emerged severe acute respiratory syndrome coronavirus (SARS-CoV) is a potent pathogen of humans and is capable of rapid global spread. Peptide-conjugated antisense morpholino oligomers (P-PMO) were designed to bind by base pairing to specific sequences in the SARS-CoV (Tor2 strain) genome. The P-PMO were tested for their capacity to inhibit production of infectious virus as well as to probe the function of conserved viral RNA motifs and secondary structures. Several virus-targeted P-PMO and a random-sequence control P-PMO showed low inhibitory activity against SARS coronavirus. Certain other virus-targeted P-PMO reduced virus-induced cytopathology and cell-to-cell spread as a consequence of decreasing viral amplification. Active P-PMO were effective when administered at any time prior to peak viral synthesis and exerted sustained antiviral effects while present in culture medium. P-PMO showed low nonspecific inhibitory activity against translation of nontargeted RNA or growth of the arenavirus lymphocytic choriomeningitis virus. Two P-PMO targeting the viral transcription-regulatory sequence (TRS) region in the 5' untranslated region were the most effective inhibitors tested. After several viral passages in the presence of a TRS-targeted P-PMO, partially drug-resistant SARS-CoV mutants arose which contained three contiguous base point mutations at the binding site of a TRS-targeted P-PMO. Those partially resistant viruses grew more slowly and formed smaller plaques than wild-type SARS-CoV. These results suggest PMO compounds have powerful therapeutic and investigative potential toward coronavirus infection.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Neuman, Benjamin W" sort="Neuman, Benjamin W" uniqKey="Neuman B" first="Benjamin W." last="Neuman">Benjamin W. Neuman</name></noRegion><name sortKey="Bestwick, Richard K" sort="Bestwick, Richard K" uniqKey="Bestwick R" first="Richard K." last="Bestwick">Richard K. Bestwick</name><name sortKey="Buchmeier, Michael J" sort="Buchmeier, Michael J" uniqKey="Buchmeier M" first="Michael J." last="Buchmeier">Michael J. Buchmeier</name><name sortKey="Churchill, Michael J" sort="Churchill, Michael J" uniqKey="Churchill M" first="Michael J." last="Churchill">Michael J. Churchill</name><name sortKey="Dawson, Philip" sort="Dawson, Philip" uniqKey="Dawson P" first="Philip" last="Dawson">Philip Dawson</name><name sortKey="Dawson, Philip" sort="Dawson, Philip" uniqKey="Dawson P" first="Philip" last="Dawson">Philip Dawson</name><name sortKey="Iversen, Patrick L" sort="Iversen, Patrick L" uniqKey="Iversen P" first="Patrick L." last="Iversen">Patrick L. Iversen</name><name sortKey="Kim, Alice M" sort="Kim, Alice M" uniqKey="Kim A" first="Alice M." last="Kim">Alice M. Kim</name><name sortKey="Kroeker, Andrew D" sort="Kroeker, Andrew D" uniqKey="Kroeker A" first="Andrew D." last="Kroeker">Andrew D. Kroeker</name><name sortKey="Kuhn, Peter" sort="Kuhn, Peter" uniqKey="Kuhn P" first="Peter" last="Kuhn">Peter Kuhn</name><name sortKey="Moulton, Hong M" sort="Moulton, Hong M" uniqKey="Moulton H" first="Hong M." last="Moulton">Hong M. Moulton</name><name sortKey="Stein, David A" sort="Stein, David A" uniqKey="Stein D" first="David A." last="Stein">David A. Stein</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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