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Designed oligomers of cyanovirin-N show enhanced HIV neutralization

Keeffe, Jennifer R. and Gnanapragasam, Priyanthi N. P. and Gillespie, Sarah K. and Yong, John and Bjorkman, Pamela J. and Mayo, Stephen L. (2011) Designed oligomers of cyanovirin-N show enhanced HIV neutralization. Proceedings of the National Academy of Sciences of the United States of America, 108 (34). pp. 14079-14084. ISSN 0027-8424. PMCID PMC3161612. http://resolver.caltech.edu/CaltechAUTHORS:20110913-132623950

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Abstract

Cyanovirin-N (CV-N) is a small, cyanobacterial lectin that neutralizes many enveloped viruses, including human immunodeficiency virus type I (HIV-1). This antiviral activity is attributed to two homologous carbohydrate binding sites that specifically bind high mannose glycosylation present on envelope glycoproteins such as HIV-1 gp120. We created obligate CV-N oligomers to determine whether increasing the number of binding sites has an effect on viral neutralization. A tandem repeat of two CV-N molecules (CVN_2) increased HIV-1 neutralization activity by up to 18-fold compared to wild-type CV-N. In addition, the CVN_2 variants showed extensive cross-clade reactivity and were often more potent than broadly neutralizing anti-HIV antibodies. The improvement in activity and broad cross-strain HIV neutralization exhibited by these molecules holds promise for the future therapeutic utility of these and other engineered CV-N variants.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1108777108DOIArticle
http://www.pnas.org/content/108/34/14079PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161612/PubMed CentralArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1108777108/-/DCSupplementalPublisherSupporting Information
ORCID:
AuthorORCID
Bjorkman, Pamela J.0000-0002-2277-3990
Contact Email Address:steve@mayo.caltech.edu
Additional Information:© 2011 National Academy of Sciences. Contributed by Stephen L. Mayo, May 31, 2011 (sent for review April 1, 2011). Published online before print July 28, 2011. We thank Leonard Thomas, Pavle Nikolovski, and the Molecular Observatory at Caltech, which is supported by the Gordon and Betty Moore Foundation, for assistance in setting up crystal trays, collecting and processing diffraction data, and refining crystal structures. We also thank the Collaboration for AIDS Vaccine Discovery Neutralizing Antibody Core Laboratories for performing HIV neutralization assays and Marie Ary for critical review of the manuscript. This work was funded by the National Security Science and Engineering Faculty Fellowship program and the Defense Advanced Research Projects Agency Protein Design Processes program (to S.L.M.) and by the Bill and Melinda Gates Foundation Grant 38660 through the Grand Challenges in Global Health Initiative (to P.J.B.). X-ray data for CVN_2L10 were collected at the Stanford Synchrotron Radiation Lightsource (Beam Line 12-2). Operations at Stanford Synchotron Radiation Lightsource are supported by the Department of Energy and the National Institutes of Health. Author contributions: J.R.K., P.J.B., and S.L.M. designed research; J.R.K., P.N.P.G., S.K.G., and J.Y. performed research; J.R.K., P.N.P.G., S.K.G., J.Y., P.J.B., and S.L.M. analyzed data; and J.R.K. wrote the paper. The authors declare no conflict of interest. Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3S3Y, 3S3Z). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1108777108/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
Gordon and Betty Moore FoundationUNSPECIFIED
National Security Science and Engineering Faculty Fellowship UNSPECIFIED
Defense Advanced Research Projects Agency (DARPA)UNSPECIFIED
Bill and Melinda Gates Foundation38660
Department of Energy (DOE)UNSPECIFIED
NIHUNSPECIFIED
Subject Keywords:crystal structure; domain-swapped dimer; protein engineering
PubMed Central ID:PMC3161612
Record Number:CaltechAUTHORS:20110913-132623950
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20110913-132623950
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:25313
Collection:CaltechAUTHORS
Deposited By: Marie Ary
Deposited On:15 Sep 2011 18:56
Last Modified:24 Mar 2017 22:21

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