@misc{10481/74732,
year = {2022},
month = {3},
url = {http://hdl.handle.net/10481/74732},
abstract = {The recognition of PPxY viral Late domains by the third WW domain of the human HECT-E3 ubiquitin ligase
NEDD4 (NEDD4-WW3) is essential for the budding of many viruses. Blocking these interactions is a promising
strategy to develop broad-spectrum antivirals. As all WW domains, NEDD4-WW3 is a challenging therapeutic
target due to the low binding affinity of its natural interactions, its high conformational plasticity, and its
complex thermodynamic behavior. In this work, we set out to investigate whether high affinity can be achieved
for monovalent ligands binding to the isolated NEDD4-WW3 domain. We show that a competitive phage-display
set-up allows for the identification of high-affinity peptides showing inhibitory activity of viral budding. A
detailed biophysical study combining calorimetry, nuclear magnetic resonance, and molecular dynamic simulations
reveals that the improvement in binding affinity does not arise from the establishment of new interactions
with the domain, but is associated to conformational restrictions imposed by a novel C-terminal -LFP motif in the
ligand, unprecedented in the PPxY interactome. These results, which highlight the complexity of WW domain
interactions, provide valuable insight into the key elements for high binding affinity, of interest to guide virtual
screening campaigns for the identification of novel therapeutics targeting NEDD4-WW3 interactions.},
organization = {Spanish Government	BIO2016-78746-C2-1-R	
PID2020-112895RB-100	
AEI/FEDER EU funds	AI138052	
AI138630},
organization = {United States Department of Health & Human Services},
organization = {National Institutes of Health (NIH) - USA	P10-CVI-5915},
organization = {German Research Foundation (DFG)},
organization = {University of Granada},
publisher = {Elsevier},
keywords = {NEDD4},
keywords = {WW domains},
keywords = {NEDD4-WW3 domain},
keywords = {Drug discovery},
keywords = {Polyproline recognition},
keywords = {Broad-spectrum antivirals},
keywords = {Phage display},
keywords = {Molecular dynamics simulations},
keywords = {Calorimetry},
keywords = {Nuclear magnetic resonance},
title = {Phage display identification of nanomolar ligands for human NEDD4-WW3: Energetic and dynamic implications for the development of broad-spectrum antivirals},
doi = {10.1016/j.ijbiomac.2022.03.010},
author = {Castillo, Francisco and Corbi Verge, Carles and Murciano Calles, Javier and Candel, Adela M. and Iglesias Bexiga, Manuel and Ruiz Sanz, Javier and Martínez Herrerías, José Cristóbal and Luque Fernández, Irene},
}