Antiviral cyclic d,l-α-peptides: Targeting a general biochemical pathway in virus infections

Abstract

Diverse virus families have evolved to exploit the acidification of endosomal compartments to gain entry into cells. We describe a supramolecular approach for selectively targeting and inhibiting viral infections through this central biochemical pathway. Using adenovirus as a model non-enveloped virus, we have determined that an eight-residue cyclic D,L-alpha-peptide, selected from a directed combinatorial library, can specifically prevent the development of low pH in endocytic vesicles, arrest the escape of virions from the endosome, and abrogate adenovirus infection without an apparent adverse effect on cell viability. The likely generality of this approach against other pH-dependent viral infections is supported by the inhibition of type-A influenza virus escape from endosomes in the presence of the same peptide. Our studies suggest that self-assembling cyclic D,L-alpha-peptides hold considerable potential as a new rational supramolecular approach toward the design and discovery of broad-spectrum antiviral agents.

Inhibition of Influenza Virus Infection by a Novel Antiviral Peptide That Targets Viral Attachment to Cells

“…More recent work has demonstrated the usefulness of peptides against numerous viral infections including respiratory syncytial virus (25), HIV (21), influenza virus (3), and general broad-spectrum antiviral activity (13). The demonstration of clinical antiviral efficacy by the HIV fusion inhibitor enfuvirtide (T-20) shows that synthetic peptides can be developed into effective antiviral drugs (21).…”

A Direct and Versatile Assay Measuring Membrane Penetration of Adenovirus in Single Cells

“…SLO-mediated perforation of the plasma membrane is used to introduce antibodies into the cytosol, and accessibility of, e.g., Alexa-488-labeled virus to anti-Alexa-488 antibodies distinguishes cytosolic from endosomal viruses in the permeabilized cells. Techniques such as delivery of cointernalized dextran or bacterial toxins into the cytosol by virus-induced rupture of endosomes (see, e.g., references 33,35,40,59, and 60), or counting of viruses at the plasma membrane, endosomes, and cytosol by EM (see, e.g., references 27, 28, and 61) have previously been used to estimate escape of HAdV-C and HAdV-B from endosomes. However, the codelivery assays are bulk assays without single-cell resolution, and most importantly, these assays estimate virus penetration only indirectly.…”

“…Furthermore, delivery of cointernalized dextran into the cytosol in HAdV-C5-infected cells has been reported to be unaffected by neutralization of endosomal pH by the vacuolar H ϩ -ATPase inhibitor bafilomycin A1 (Baf A1) (33). On the other hand, inhibition of endosomal acidification has been reported to reduce cytosolic delivery of cointernalized bacterial toxins (35,40,41) and overall viral infection efficiency (15,42). However, none of these studies directly monitored cytosolic and endosomal virus populations in the infected cells.…”

Self–Assembled Peptide Nanostructures for Biomedical Applications: Advantages and Challenges

“…These applications have been reviewed in numerous articles (Aggeli et al, 2001, Gao & Matsui, 2005, Gazit, 2007, Hauser & Zhang, 2010, Kyle et al, 2010, Kyle et al, 2008, Rajagopal & Schneider, 2004, Scanlon & Aggeli, 2008, Woolfson & Ryadnov, 2006, Yan et al, 2010, and a detailed description of some of these applications has already been given in this chapter. In order to provide a broader vision of the possibilities of using these biological nanostructures with biomedical purposes, a list of different self-assembled peptide nanostructures is presented in (Cho et al, 2008) Nanotubes Glucose, ethanol and hydrogen peroxide detection Nanotubes Antiviral agent (Horne et al, 2005) Nanotubes Controlled drug release (Chen et al, 2011) Nanotubes Hydrogen peroxide detection (Cipriano et al, 2010) Nanotubes Drug delivery (von Maltzahn et al, 2003) Nanofibers Copper detection (Viguier et al, 2011) Nanofibers Dopamine detection (Sasso et al, 2011) Nanofibers Yersinia pestis detection (Men et al, 2010) Nanofibers Glucose detection (Yang et al, 2009) …”