A Positional Scanning Combinatorial Library of Peptoids As a Source of Biological Active Molecules:  Identification of Antimicrobials

2003 ◽  
Vol 5 (5) ◽  
pp. 597-605 ◽  
Author(s):  
Marc Humet ◽  
Teresa Carbonell ◽  
Isabel Masip ◽  
Francisco Sánchez-Baeza ◽  
Puig Mora ◽  
...  
Keyword(s):  
Combinatorial Library ◽  
Positional Scanning

scholarly journals Non-combinatorial library screening reveals subsite cooperativity and identifies new high-efficiency substrates for kallikrein-related peptidase 14

2012 ◽  
Vol 393 (5) ◽  
pp. 331-341 ◽  
Author(s):  
Simon J. de Veer ◽  
Joakim E. Swedberg ◽  
Edward A. Parker ◽  
Jonathan M. Harris
Keyword(s):  
Binding Site ◽  
Combinatorial Library ◽  
High Efficiency ◽  
Sparse Matrix ◽  
Screening Methods ◽  
Optimal Sequence ◽  
Protease Cleavage ◽  
Positional Scanning ◽  
Active Site Cleft ◽  
Protease Substrate

Abstract An array of substrates link the tryptic serine protease, kallikrein-related peptidase 14 (KLK14), to physiological functions including desquamation and activation of signaling molecules associated with inflammation and cancer. Recognition of protease cleavage sequences is driven by complementarity between exposed substrate motifs and the physicochemical signature of an enzyme’s active site cleft. However, conventional substrate screening methods have generated conflicting subsite profiles for KLK14. This study utilizes a recently developed screening technique, the sparse matrix library, to identify five novel high-efficiency sequences for KLK14. The optimal sequence, YASR, was cleaved with higher efficiency (kcat/Km=3.81±0.4×106 m-1 s-1) than favored substrates from positional scanning and phage display by 2- and 10-fold, respectively. Binding site cooperativity was prominent among preferred sequences, which enabled optimal interaction at all subsites as indicated by predictive modeling of KLK14/substrate complexes. These simulations constitute the first molecular dynamics analysis of KLK14 and offer a structural rationale for the divergent subsite preferences evident between KLK14 and closely related KLKs, KLK4 and KLK5. Collectively, these findings highlight the importance of binding site cooperativity in protease substrate recognition, which has implications for discovery of optimal substrates and engineering highly effective protease inhibitors.

scholarly journals Identification of novel cyclic lipopeptides from a positional scanning combinatorial library with enhanced antibacterial and antibiofilm activities

2016 ◽  
Vol 108 ◽  
pp. 354-363 ◽  
Author(s):  
Nina Bionda ◽  
Renee M. Fleeman ◽  
César de la Fuente-Núñez ◽  
Maria C. Rodriguez ◽  
Fany Reffuveille ◽  
...  
Keyword(s):  
Combinatorial Library ◽  
Cyclic Lipopeptides ◽  
Positional Scanning

scholarly journals Identification of novel antimelanogenic hexapeptides via positional scanning of a synthetic peptide combinatorial library

2017 ◽  
Vol 26 (8) ◽  
pp. 742-744 ◽  
Author(s):  
Jin K. Seok ◽  
Seok W. Lee ◽  
Jaehyuk Choi ◽  
Young M. Kim ◽  
Yong C. Boo
Keyword(s):  
Synthetic Peptide ◽  
Combinatorial Library ◽  
Positional Scanning

scholarly journals Mixture-Based Heterocyclic Combinatorial Positional Scanning Libraries: Discovery of Bicyclic Guanidines Having Potent Antifungal Activities against Candida albicans andCryptococcus neoformans

1999 ◽  
Vol 43 (1) ◽  
pp. 106-114 ◽  
Author(s):  
Sylvie E. Blondelle ◽  
Ema Crooks ◽  
John M. Ostresh ◽  
Richard A. Houghten
Keyword(s):  
Candida Albicans ◽  
Heterocyclic Compounds ◽  
Combinatorial Library ◽  
Rapid Identification ◽  
Positional Scanning ◽  
Bactericidal Activities ◽  
Kill Curve ◽  
The Individual ◽  
Time Kill ◽  
Positional Scanning Libraries

ABSTRACT A mixture-based synthetic combinatorial library of more than 100,000 bicyclic guanidines was generated in a positional scanning format and assayed for activity against Candida albicans. Potent individual bicyclic guanidines were directly identified following the screening of the library. Time-kill curve studies indicated bactericidal activities for the individual bicyclic guanidines. These compounds also showed potent activity againstCryptococcus neoformans. These studies demonstrate the value of using mixture-based combinatorial positional scanning libraries made up of heterocyclic compounds for the rapid identification of novel classes of antifungal compounds.

scholarly journals Dissecting MMP P10′ and P11′ subsite sequence preferences, utilizing a positional scanning, combinatorial triple-helical peptide library

2018 ◽  
Vol 293 (43) ◽  
pp. 16661-16676 ◽  
Author(s):  
Michal Tokmina-Roszyk ◽  
Gregg B. Fields
Keyword(s):  
Enzyme Activity ◽  
Tumor Invasion ◽  
Combinatorial Library ◽  
Peptide Inhibitors ◽  
Invasion And Metastasis ◽  
Enzyme Activity Assay ◽  
Peptide Mimic ◽  
Helical Peptide ◽  
Positional Scanning

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that remodel the extracellular matrix environment and mitigate outside-in signaling. Loss of regulation of MMP activity plays a role in numerous pathological states. In particular, aberrant collagenolysis affects tumor invasion and metastasis, osteoarthritis, and cardiovascular and neurodegenerative diseases. To evaluate the collagen sequence preferences of MMPs, a positional scanning synthetic combinatorial library was synthesized herein and was used to investigate the P10′ and P11′ substrate subsites. The scaffold for the library was a triple-helical peptide mimic of the MMP cleavage site in types I–III collagen. A FRET-based enzyme activity assay was used to evaluate the sequence preferences of eight MMPs. Deconvolution of the library data revealed distinct motifs for several MMPs and discrimination among closely related MMPs. On the basis of the screening results, several individual peptides were designed and evaluated. A triple-helical substrate incorporating Asp–Lys in the P10′–P11′ subsites offered selectivity between MMP-14 and MMP-15, whereas Asp–Lys or Trp–Lys in these subsites discriminated between MMP-2 and MMP-9. Future screening of additional subsite positions will enable the design of selective triple-helical MMP probes that could be used for monitoring in vivo enzyme activity and enzyme-facilitated drug delivery. Furthermore, selective substrates could serve as the basis for the design of specific triple-helical peptide inhibitors targeting only those MMPs that play a detrimental role in a disease of interest.

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