Design of Heptad Repeat Amphiphiles Based on Database Filtering and Structure–Function Relationships to Combat Drug-Resistant Fungi and Biofilms

2019 ◽  
Vol 12 (2) ◽  
pp. 2129-2144 ◽  
Author(s):  
Peng Tan ◽  
Zhenheng Lai ◽  
Qiao Jian ◽  
Changxuan Shao ◽  
Yongjie Zhu ◽  
...  
Keyword(s):  
Structure Function ◽  
Heptad Repeat ◽  
Drug Resistant ◽  
Database Filtering

scholarly journals Structure–function study of cathelicidin-derived bovine antimicrobial peptide BMAP-28: Design of its cell-selective analogs by amino acid substitutions in the heptad repeat sequences

2009 ◽  
Vol 1788 (11) ◽  
pp. 2411-2420 ◽  
Author(s):  
Aqeel Ahmad ◽  
Neeta Asthana ◽  
Sarfuddin Azmi ◽  
Raghvendra M. Srivastava ◽  
Brijesh K. Pandey ◽  
...  
Keyword(s):  
Amino Acid ◽  
Antimicrobial Peptide ◽  
Structure Function ◽  
Heptad Repeat ◽  
Amino Acid Substitutions ◽  
Repeat Sequences ◽  
Function Study

scholarly journals Mechanism of HIV-1 Resistance to Short-Peptide Fusion Inhibitors Targeting the Gp41 Pocket

2015 ◽  
Vol 89 (11) ◽  
pp. 5801-5811 ◽  
Author(s):  
Yang Su ◽  
Huihiui Chong ◽  
Zonglin Qiu ◽  
Shengwen Xiong ◽  
Yuxian He
Keyword(s):  
Structure Function ◽  
Heptad Repeat ◽  
Cross Resistance ◽  
Short Peptide ◽  
Fusion Inhibitors ◽  
Structure Function Relationship ◽  
Underlying Mechanisms ◽  
Function Relationship ◽  
Relationship Of ◽  
Hiv 1

ABSTRACTThe deep hydrophobic pocket on the N trimer of HIV-1 gp41 has been considered an ideal drug target. On the basis of the M-T hook structure, we recently developed short-peptide-based HIV-1 fusion inhibitors (MTSC22 and HP23), which mainly target the pocket site and possess highly potent antiviral activity. In this study, we focused on investigating their resistance pathways and mechanisms by escape HIV-1 mutants to SC22EK, a template peptide for MTSC22 and HP23. Two substitutions, E49K and N126K, located, respectively, at the N- and C-heptad repeat regions of gp41, were identified as conferring high resistance to the inhibitors targeting the pocket and cross-resistance to enfuvirtide (T20) and sifuvirtide (SFT). The underlying mechanisms of SC22EK-induced resistance include the following: (i) significantly reduced binding affinity of the inhibitors, (ii) dramatically enhanced interaction of the viral six-helix bundle, and (iii)severely damaged functionality of the viral Env complex. Our data have provided important information for the structure-function relationship of gp41 and the structure-activity relationship of viral fusion inhibitors.IMPORTANCEEnfuvirtide (T20) is the only HIV-1 fusion inhibitor in clinical use, but the problem of resistance significantly limits its use, calling for new strategies or concepts to develop next-generation drugs. On the basis of the M-T hook structure, short-peptide HIV-1 fusion inhibitors specifically targeting the gp41 pocket site exhibit high binding and antiviral activities. Here, we investigated the molecular pathway of HIV-1 resistance to the short inhibitors by selecting and mapping the escape mutants. The key substitutions for resistance and the underlying mechanisms have been finely characterized. The data provide important information for the structure-function relationship of gp41 and its inhibitors and will definitely help our future development of novel drugs that block gp41-dependent fusion.

scholarly journals Recent insights into the structure and function of Mitofusins in mitochondrial fusion

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1983 ◽  
Author(s):  
Mickael M Cohen ◽  
David Tareste
Keyword(s):  
Structure Function ◽  
Membrane Fusion ◽  
Mode Of Action ◽  
Structure And Function ◽  
Transmembrane Domains ◽  
Mitochondrial Fusion ◽  
Heptad Repeat ◽  
Mitochondrial Membranes ◽  
Function Data ◽  
And Function

Mitochondria undergo frequent fusion and fission events to adapt their morphology to cellular needs. Homotypic docking and fusion of outer mitochondrial membranes are controlled by Mitofusins, a set of large membrane-anchored GTPase proteins belonging to the dynamin superfamily. Mitofusins include, in addition to their GTPase and transmembrane domains, two heptad repeat domains, HR1 and HR2. All four regions are crucial for Mitofusin function, but their precise contribution to mitochondrial docking and fusion events has remained elusive until very recently. In this commentary, we first give an overview of the established strategies employed by various protein machineries distinct from Mitofusins to mediate membrane fusion. We then present recent structure–function data on Mitofusins that provide important novel insights into their mode of action in mitochondrial fusion.

scholarly journals Structure–Function Aspects of PstS in Multi-Drug–Resistant Pseudomonas aeruginosa

2008 ◽  
Vol 4 (2) ◽  
pp. e43 ◽  
Author(s):  
Olga Zaborina ◽  
Christopher Holbrook ◽  
Yimei Chen ◽  
Jason Long ◽  
Alexander Zaborin ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Structure Function ◽  
Drug Resistant

scholarly journals Coronavirus Escape from Heptad Repeat 2 (HR2)-Derived Peptide Entry Inhibition as a Result of Mutations in the HR1 Domain of the Spike Fusion Protein

2007 ◽  
Vol 82 (5) ◽  
pp. 2580-2585 ◽  
Author(s):  
Berend Jan Bosch ◽  
John W. A. Rossen ◽  
Willem Bartelink ◽  
Stephanie J. Zuurveen ◽  
Cornelis A. M. de Haan ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Inhibitory Effect ◽  
Cell Entry ◽  
Heptad Repeat ◽  
Drug Resistant ◽  
Viral Fusion ◽  
Main Determinant ◽  
Viral Fusion Proteins ◽  
Inhibitor Drug ◽  
Entry Inhibition

ABSTRACT Peptides based on heptad repeat (HR) domains of class I viral fusion proteins are considered promising antiviral drugs targeting virus cell entry. We have analyzed the evolution of the mouse hepatitis coronavirus during multiple passaging in the presence of an HR2-based fusion inhibitor. Drug-resistant variants emerged as a result of multiple substitutions in the spike fusion protein, notably within a 19-residue segment of the HR1 region. Strikingly, one mutation, an A1006V substitution, which consistently appeared first in four independently passaged viruses, was the main determinant of the resistance phenotype, suggesting that only limited options exist for escape from the inhibitory effect of the HR2 peptide.

scholarly journals Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria

2018 ◽  
Vol 25 (4) ◽  
pp. 380-391.e5 ◽  
Author(s):  
Tony Velkov ◽  
Alejandra Gallardo-Godoy ◽  
James D. Swarbrick ◽  
Mark. A.T. Blaskovich ◽  
Alysha G. Elliott ◽  
...  
Keyword(s):  
Structure Function ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Gram Negative ◽  
Extensively Drug Resistant

scholarly journals Structure-Function Study of a Heptad Repeat Positioned Near the Transmembrane Domain of Sendai Virus Fusion Protein Which Blocks Virus-Cell Fusion

1998 ◽  
Vol 273 (42) ◽  
pp. 27182-27190 ◽  
Author(s):  
Jimut Kanti Ghosh ◽  
Sergio Gerardo Peisajovich ◽  
Michael Ovadia ◽  
Yechiel Shai
Keyword(s):  
Fusion Protein ◽  
Structure Function ◽  
Cell Fusion ◽  
Transmembrane Domain ◽  
Sendai Virus ◽  
Heptad Repeat ◽  
Function Study ◽  
Virus Fusion
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