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Antimicrobial Agents and Chemotherapy, June 2008, p. 2079-2088, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01415-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Multivalent Presentation of Antihantavirus Peptides on Nanoparticles Enhances Infection Blockade{triangledown}

Pamela R. Hall, Brian Hjelle, David C. Brown, Chunyan Ye, Virginie Bondu-Hawkins, Kathleen A. Kilpatrick, and Richard S. Larson*

Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131

Received 1 November 2007/ Returned for modification 17 December 2007/ Accepted 28 March 2008

Viral entry into susceptible host cells typically results from multivalent interactions between viral surface proteins and host entry receptors. In the case of Sin Nombre virus (SNV), a New World hantavirus that causes hantavirus cardiopulmonary syndrome, infection involves the interaction between viral membrane surface glycoproteins and the human integrin {alpha}vβ3. Currently, there are no therapeutic agents available which specifically target SNV. To address this problem, we used phage display selection of cyclic nonapeptides to identify peptides that bound SNV and specifically prevented SNV infection in vitro. We synthesized cyclic nonapeptides based on peptide sequences of phage demonstrating the strongest inhibition of infection, and in all cases, the isolated peptides were less effective at blocking infection (9.0% to 27.6% inhibition) than were the same peptides presented by phage (74.0% to 82.6% inhibition). Since peptides presented by the phage were pentavalent, we determined whether the identified peptides would show greater inhibition if presented in a multivalent format. We used carboxyl linkages to conjugate selected cyclic peptides to multivalent nanoparticles and tested infection inhibition. Two of the peptides, CLVRNLAWC and CQATTARNC, showed inhibition that was improved over that of the free format when presented on nanoparticles at a 4:1 nanoparticle-to-virus ratio (9.0% to 32.5% and 27.6% to 37.6%, respectively), with CQATTARNC inhibition surpassing 50% when nanoparticles were used at a 20:1 ratio versus virus. These data illustrate that multivalent inhibitors may disrupt polyvalent protein-protein interactions, such as those utilized for viral infection of host cells, and may represent a useful therapeutic approach.

* Corresponding author. Mailing address: UNM School of Medicine, 2325 Camino de Salud, CRF 223, Albuquerque, NM 87131. Phone: (505) 272-6950. Fax: (505) 272-8738. E-mail: RLarson{at}salud.unm.edu

{triangledown} Published ahead of print on 7 April 2008.

Antimicrobial Agents and Chemotherapy, June 2008, p. 2079-2088, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01415-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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