caa a22 4500 445326514 CHVBK 20180317142722.0 cr unu---uuuuu 170323e20111201xx s 000 0 eng 10.1007/s10989-011-9272-x doi (NATIONALLICENCE)springer-10.1007/s10989-011-9272-x Simplified θ-Defensins: Search for New Antivirals [Elektronische Daten] [Piotr Ruchala, Sylvia Cho, Amy Cole, Colleen Carpenter, Chun-Ling Jung, Hai Luong, Ewa Micewicz, Alan Waring, Alexander Cole, Betsy Herold, Robert Lehrer] Peptides of the innate immune system provide intriguing templates for designing novel antiviral molecules. θ-defensins are nonhuman primate peptides with broad-spectrum antiviral activities. The activity of these compounds is mediated through interference with viral fusion, and this activity is based upon key structural features. However, two major limitations to their clinical use hampered their development as potential antivirals, namely difficult multi-step synthesis for their production with low final yield of desired product (~5%), and unfavorable pharmacokinetics (rapid enzymatic degradation and/or renal clearance). Recently we designed and screened two sub-libraries of new peptide-based entry inhibitors mimicking the structure of humanized θ-defensins, designated as Hapivirins (HpVs) and Diprovirins (DpVs). Although the new peptides are smaller (13-residues) and structurally more simple than retrocyclins, several retained their ability to protect cells from infection by HIV-1 and HSV-2. The most active compound, DpV16, was chosen for a second round of modifications based on (1) its potent antiviral activity (2) its ease of synthesis, and (3) the low cost of production. Subsequently, we created a library of a second generation DpV-analogues with enhanced properties. Collectively, our findings to date suggest that simplified θ-defensins are suitable candidates for further modifications to obtain analogues with clinically favorable pharmacokinetics that may be produced in large quantities using a standard chemical approach. Considering their small size, they could be used either topically (topical microbicides) and/or for systemic applications (entry inhibitors). Springer Science+Business Media, LLC, 2011 Peptides nationallicence Defensins nationallicence Antivirals nationallicence HIV-1 nationallicence HSV-2 nationallicence Ruchala Piotr Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095, Los Angeles, CA, USA aut Cho Sylvia Department of Pediatrics and Microbiology-Immunology, Albert Einstein College of Medicine of Yeshiva University, 10461, New York, NY, USA aut Cole Amy Department of Molecular Biology and Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 32816, Orlando, FL, USA aut Carpenter Colleen Department of Pediatrics and Microbiology-Immunology, Albert Einstein College of Medicine of Yeshiva University, 10461, New York, NY, USA aut Jung Chun-Ling Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095, Los Angeles, CA, USA aut Luong Hai Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095, Los Angeles, CA, USA aut Micewicz Ewa Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095, Los Angeles, CA, USA aut Waring Alan Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095, Los Angeles, CA, USA aut Cole Alexander Department of Molecular Biology and Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 32816, Orlando, FL, USA aut Herold Betsy Department of Pediatrics and Microbiology-Immunology, Albert Einstein College of Medicine of Yeshiva University, 10461, New York, NY, USA aut Lehrer Robert Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095, Los Angeles, CA, USA aut International Journal of Peptide Research and Therapeutics Springer Netherlands 17/4(2011-12-01), 325-336 1573-3149 17:4<325 2011 17 10989 https://doi.org/10.1007/s10989-011-9272-x text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10989-011-9272-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Ruchala Piotr Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Cho Sylvia Department of Pediatrics and Microbiology-Immunology, Albert Einstein College of Medicine of Yeshiva University, 10461, New York, NY, USA aut NATIONALLICENCE 700 1- Cole Amy Department of Molecular Biology and Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 32816, Orlando, FL, USA aut NATIONALLICENCE 700 1- Carpenter Colleen Department of Pediatrics and Microbiology-Immunology, Albert Einstein College of Medicine of Yeshiva University, 10461, New York, NY, USA aut NATIONALLICENCE 700 1- Jung Chun-Ling Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Luong Hai Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Micewicz Ewa Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Waring Alan Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Cole Alexander Department of Molecular Biology and Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 32816, Orlando, FL, USA aut NATIONALLICENCE 700 1- Herold Betsy Department of Pediatrics and Microbiology-Immunology, Albert Einstein College of Medicine of Yeshiva University, 10461, New York, NY, USA aut NATIONALLICENCE 700 1- Lehrer Robert Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095, Los Angeles, CA, USA aut NATIONALLICENCE 773 0- International Journal of Peptide Research and Therapeutics Springer Netherlands 17/4(2011-12-01), 325-336 1573-3149 17:4<325 2011 17 10989 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer