Cyanovirin-N (CVN)

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'''Microbial Antiviral Proteins with GBP Activity'''<br>
'''Microbial Antiviral Proteins with GBP Activity'''<br>
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Antiviral compounds made by eukaryotes that recognize unique glycan determinants represent a new paradigm in terms of understanding the innate immune system of primitive organisms and how that might relate to mammalian innate immune systems. Many mammalian GBPs act as innate immune defenders, including the C-type lectins mannose-binding protein and other collectins. Interestingly, many of these bind glycan determinants common often relatively rish in mannose and/or fucose. It is interesting that one of the most promising anti-HIV-1 drugs in development is the cyanovirin-N from blue-green algae. While CVN was originally thought to be an orphan lectin with little homology to any other known protein family (Koharudin, et al. 2008), recently a family of CVN homologous proteins termed cyanovirin-N homologs (CVNHs), were found in multicellular ascomycetous fungi and in the fern Ceratopteris richardii (Percudani, et al. 2005).  These proteins share 3-D structural elements (Koharudin, et al. 2008). Interestingly, a prokaryotic homolog of CVN, termed MVN was found in the toxin-producing cyanobacterium Microcystis aeruginosa and MVN also binds high mannose-type glycans (Kehr, et al. 2006). Defining the glycan binding specificity and mode of action of these interesting virucidal proteins may help to develop a range of new drug therapies for human viral infections.
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Antiviral compounds made by eukaryotes that recognize unique glycan determinants represent a new paradigm in terms of understanding the innate immune system of primitive organisms and how that might relate to mammalian innate immune systems. Many mammalian GBPs act as innate immune defenders, including the C-type lectins mannose-binding protein and other collectins. Interestingly, many of these bind glycan determinants common often relatively rish in mannose and/or fucose. It is interesting that one of the most promising anti-HIV-1 drugs in development is the cyanovirin-N from blue-green algae. While CVN was originally thought to be an orphan lectin with little homology to any other known protein family<ref name="Koharudin 2008">Koharudin, L.M., Viscomi, A.R., Jee, J.G., Ottonello, S. and Gronenborn, A.M. 2008. The evolutionarily conserved family of cyanovirin-N homologs: structures and carbohydrate specificity. Structure, 16, 570-584.</ref>, recently a family of CVN homologous proteins termed cyanovirin-N homologs (CVNHs), were found in multicellular ascomycetous fungi and in the fern ''Ceratopteris richardii''<ref>Percudani, R., Montanini, B. and Ottonello, S. 2005. The anti-HIV cyanovirin-N domain is evolutionarily conserved and occurs as a protein module in eukaryotes. Proteins, 60, 670-678.</ref>.  These proteins share 3-D structural elements<ref name="Koharudin 2008"/>. Interestingly, a prokaryotic homolog of CVN, termed MVN was found in the toxin-producing cyanobacterium Microcystis aeruginosa and MVN also binds high mannose-type glycans<ref>Kehr, J.C., Zilliges, Y., Springer, A., Disney, M.D., Ratner, D.D., Bouchier, C., Seeberger, P.H., de Marsac, N.T. and Dittmann, E. 2006. A mannan binding lectin is involved in cell-cell attachment in a toxic strain of Microcystis aeruginosa. Mol Microbiol, 59, 893-906.</ref>. Defining the glycan binding specificity and mode of action of these interesting virucidal proteins may help to develop a range of new drug therapies for human viral infections.
'''Cyanovirin-N'''  (''Nostoc ellipsosporum'' - a cyanobacterium; blue-green alga)<br>
'''Cyanovirin-N'''  (''Nostoc ellipsosporum'' - a cyanobacterium; blue-green alga)<br>
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Cyanovirin-N (CVN) was chosen as a paradigm because of its relevance to human disease and potentially new virucidals found in nature. CVN is an virucidal compound originally isolated from cyanobacterium Nostoc ellipsosporum, a blue-green algae (Boyd, et al. 1997) in screening for anti-HIV activities. CVN is a small protein of 101 amino acids with two internal tandem repeats of ~50 amino acids with no significant homology to any other known protein. CVN exists as a dimer and each subunit has two independent glycan binding sites. CVN binds with high affinity the envelope glycoprotein gp120 of HIV-1 and inhibits virus entry into cells. The evidence indicates that its binding occurs to high mannose-type N-glycans on the glycoprotein. However, CVN also binds to other enveloped viruses, such as SIV, Ebola, influenza and hepatitis C. Thus, CVN represents a new paradigm of microbial GBPs, wherein a unique glycan binding domain comprised of two approximately 50 amino acids regions, exhibit extreme specificity toward specific α-mannose-type N-glycan structures containing multiple α-2-linked mannose residues.
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Cyanovirin-N (CVN) was chosen as a paradigm because of its relevance to human disease and potentially new virucidals found in nature. CVN is an virucidal compound originally isolated from cyanobacterium Nostoc ellipsosporum, a blue-green algae<ref>Boyd, M.R., Gustafson, K.R., McMahon, J.B., Shoemaker, R.H., O'Keefe, B.R., Mori, T., Gulakowski, R.J., Wu, L., Rivera, M.I., Laurencot, C.M., Currens, M.J., Cardellina, J.H., 2nd, Buckheit, R.W., Jr., Nara, P.L., Pannell, L.K., Sowder, R.C., 2nd and Henderson, L.E. 1997. Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide
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development. Antimicrob Agents Chemother, 41, 1521-1530.</ref> in screening for anti-HIV activities. CVN is a small protein of 101 amino acids with two internal tandem repeats of ~50 amino acids with no significant homology to any other known protein. CVN exists as a dimer and each subunit has two independent glycan binding sites. CVN binds with high affinity the envelope glycoprotein gp120 of HIV-1 and inhibits virus entry into cells. The evidence indicates that its binding occurs to high mannose-type N-glycans on the glycoprotein. However, CVN also binds to other enveloped viruses, such as SIV, Ebola, influenza and hepatitis C. Thus, CVN represents a new paradigm of microbial GBPs, wherein a unique glycan binding domain comprised of two approximately 50 amino acids regions, exhibit extreme specificity toward specific α-mannose-type N-glycan structures containing multiple α-2-linked mannose residues.
== CFG Participating Investigators contributing to the understanding of this paradigm ==
== CFG Participating Investigators contributing to the understanding of this paradigm ==

Revision as of 04:57, 10 April 2010

Microbial Antiviral Proteins with GBP Activity
Antiviral compounds made by eukaryotes that recognize unique glycan determinants represent a new paradigm in terms of understanding the innate immune system of primitive organisms and how that might relate to mammalian innate immune systems. Many mammalian GBPs act as innate immune defenders, including the C-type lectins mannose-binding protein and other collectins. Interestingly, many of these bind glycan determinants common often relatively rish in mannose and/or fucose. It is interesting that one of the most promising anti-HIV-1 drugs in development is the cyanovirin-N from blue-green algae. While CVN was originally thought to be an orphan lectin with little homology to any other known protein family[1], recently a family of CVN homologous proteins termed cyanovirin-N homologs (CVNHs), were found in multicellular ascomycetous fungi and in the fern Ceratopteris richardii[2]. These proteins share 3-D structural elements[1]. Interestingly, a prokaryotic homolog of CVN, termed MVN was found in the toxin-producing cyanobacterium Microcystis aeruginosa and MVN also binds high mannose-type glycans[3]. Defining the glycan binding specificity and mode of action of these interesting virucidal proteins may help to develop a range of new drug therapies for human viral infections.

Cyanovirin-N (Nostoc ellipsosporum - a cyanobacterium; blue-green alga)
Cyanovirin-N (CVN) was chosen as a paradigm because of its relevance to human disease and potentially new virucidals found in nature. CVN is an virucidal compound originally isolated from cyanobacterium Nostoc ellipsosporum, a blue-green algae[4] in screening for anti-HIV activities. CVN is a small protein of 101 amino acids with two internal tandem repeats of ~50 amino acids with no significant homology to any other known protein. CVN exists as a dimer and each subunit has two independent glycan binding sites. CVN binds with high affinity the envelope glycoprotein gp120 of HIV-1 and inhibits virus entry into cells. The evidence indicates that its binding occurs to high mannose-type N-glycans on the glycoprotein. However, CVN also binds to other enveloped viruses, such as SIV, Ebola, influenza and hepatitis C. Thus, CVN represents a new paradigm of microbial GBPs, wherein a unique glycan binding domain comprised of two approximately 50 amino acids regions, exhibit extreme specificity toward specific α-mannose-type N-glycan structures containing multiple α-2-linked mannose residues.

Contents

CFG Participating Investigators contributing to the understanding of this paradigm

CFG Participating Investigators (PIs) who have contributed to studies of this paradigmatic protein include: Simone Ottonello

Progress toward understanding this GBP paradigm

Carbohydrate ligands


Cellular expression


Structure


Biological roles of GBP-ligand interaction


CFG resources used in investigations

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for "cyanovirin-N".

Glycan profiling


Glycogene microarray


Knockout mouse lines


Glycan array

The CFG has contributed glycans and conducted glycan array screening for CVN ligand specificities.

Related GBPs

The large family of CVNHs found in both eukaryotic fungi and cyanobacteria.

References

  1. 1.0 1.1 Koharudin, L.M., Viscomi, A.R., Jee, J.G., Ottonello, S. and Gronenborn, A.M. 2008. The evolutionarily conserved family of cyanovirin-N homologs: structures and carbohydrate specificity. Structure, 16, 570-584.
  2. Percudani, R., Montanini, B. and Ottonello, S. 2005. The anti-HIV cyanovirin-N domain is evolutionarily conserved and occurs as a protein module in eukaryotes. Proteins, 60, 670-678.
  3. Kehr, J.C., Zilliges, Y., Springer, A., Disney, M.D., Ratner, D.D., Bouchier, C., Seeberger, P.H., de Marsac, N.T. and Dittmann, E. 2006. A mannan binding lectin is involved in cell-cell attachment in a toxic strain of Microcystis aeruginosa. Mol Microbiol, 59, 893-906.
  4. Boyd, M.R., Gustafson, K.R., McMahon, J.B., Shoemaker, R.H., O'Keefe, B.R., Mori, T., Gulakowski, R.J., Wu, L., Rivera, M.I., Laurencot, C.M., Currens, M.J., Cardellina, J.H., 2nd, Buckheit, R.W., Jr., Nara, P.L., Pannell, L.K., Sowder, R.C., 2nd and Henderson, L.E. 1997. Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development. Antimicrob Agents Chemother, 41, 1521-1530.

Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page:

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