The current standard of care consists of prophylactic treatment of at-risk infants with palivizumab (Synagis), a monoclonal antibody that is administered monthly as an injectable during the peak season of infection (typically, November to March in Europe and in the United States). In addition, the virus is also increasingly recognized as an important pathogen in the elderly population as well as in bone marrow transplant recipients ( 4). A recent study performed by Pneumonia Etiology Research for Child Health (PERCH) across 7 countries revealed that RSV was the reason for hospitalization for 31% of all children hospitalized with severe pneumonia ( 3). In the United States, it has been estimated that RSV is responsible for 86,000 child hospitalizations per year, with an estimated cost of $394 million ( 2). In 2005, RSV caused almost 34 million cases of lower respiratory infections in children under 5 years of age, with 3 to 10% of them requiring hospitalization, accounting for 45% of the total child admissions ( 1). doi:10.1158/1538-7445.Respiratory syncytial virus (RSV) is very contagious and represents the main cause of severe acute respiratory tract illness in young children worldwide. Philadelphia (PA): AACR Cancer Res 2013 73(8 Suppl):Abstract nr 3340. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research 2013 Apr 6-10 Washington, DC. Stapled helix peptides as probes to evaluate targeted disruption of protein-protein interactions mediated by RPA70N. In this study, we further examine the functional consequences of RPA70N disruption by ATRIP-derived hydrocarbon stapled peptides and discuss the use of them as tools to probe the therapeutic relevance of RPA inhibition in breast and other cancers.Ĭitation Format: Bhavatarini Vangamudi, Andreas O. The optimized peptide was cell penetrant, able to enter the nucleus, and co-localized with RPA in the nucleus at sites of DNA damage. Based on the alanine scan data, two positions were chosen for incorporation of a hydrocarbon staple however, only one of these stapled peptides maintained binding affinity for RPA70N. The resulting peptide, chosen for stapling, represented a balance between net charge and potency and was intended to offer the best chance of cell penetration while still maintaining affinity. In most instances, residues that improved the net charge had a deleterious effect on binding affinity. To facilitate entry into cells, negatively charged residues were replaced by alanines or by neutral, polar residues. Introduction of a conserved WFA motif derived from analysis of the p53-binding sequence produced a 10-fold gain in potency over the native ATRIP peptide. In addition, the scan revealed residue positions that were dispensable and therefore suitable as sites for incorporation of a staple. Here, we report the development of a potent stapled helix peptide probe, derived from the endogenous RPA binding partner ATRIP (ATR-interacting protein), that binds to and inhibits the RPA70N protein-protein interaction surface.Īn initial alanine scan of the native ATRIP-derived sequence identified residues critical for peptide binding to RPA70N. Incorporation of a hydrocarbon “staple” has the potential to increase the potency, stability, and cell permeability of peptides. Stapled helix peptides are an emerging technology for the inhibition of protein-protein interactions. Specific disruption of the RPA protein-protein interactions mediated by the RPA70N domain has the potential to produce selective killing of cancer cells without the risk of cytotoxicity due to interference in the ssDNA-binding function. In response to genotoxic stress, the RPA complex binds to and protects ssDNA while serving as a scaffold to recruit critical checkpoint and DNA-damage response proteins through the N-terminal region of the 70 kDa subunit of RPA (RPA70N). Replication Protein A (RPA) is a major regulator of checkpoint activation and enhanced DNA repair in cancer cells.
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