scholarly journals Macrocyclic peptides that inhibit Wnt signalling via interaction with Wnt3a

2020 ◽  
Vol 1 (1) ◽  
pp. 26-34
Author(s):  
Manuel E. Otero-Ramirez ◽  
Kyoko Matoba ◽  
Emiko Mihara ◽  
Toby Passioura ◽  
Junichi Takagi ◽  
...  
Keyword(s):  
De Novo ◽  
Direct Interaction ◽  
Wnt Signalling ◽  
Rapid Screening ◽  
Macrocyclic Peptides ◽  
Macrocyclic Peptide

Discovery and optimization of de novo macrocyclic peptide binders of Wnt3a through RaPID screening against an afamin-stabilized Wnt3a complex, capable of inhibiting Wnt signalling by direct interaction to the Wnt protein.

scholarly journals Conformational interplay in hybrid peptide-helical aromatic foldamer macrocycles

2021 ◽  
Author(s):  
Sebastian Dengler ◽  
Pradeep Kumar Mandal ◽  
Lars Allmendinger ◽  
Céline Douat ◽  
Ivan Huc
Keyword(s):  
Important Class ◽  
Hybrid Peptide ◽  
Bioactive Substances ◽  
Macrocyclic Peptides ◽  
Macrocyclic Peptide

Macrocyclic peptides are an important class of bioactive substances. When inserting an aromatic foldamer segment in a macrocyclic peptide, the strong folding propensity of the former may influence the conformation...

scholarly journals miR-128-induced LINE-1 restriction is dependent on down-regulation of hnRNPA1

2017 ◽  
Author(s):  
Lianna Fung ◽  
Herlinda Guzman ◽  
Evgueni Sevrioukov ◽  
Adam Idica ◽  
Eddie Park ◽  
...  
Keyword(s):  
Target Genes ◽  
De Novo ◽  
Somatic Cells ◽  
Direct Interaction ◽  
Life Cycles ◽  
Genomic Diversity ◽  
Protein Levels ◽  
Induced Mutagenesis ◽  
Genomic Locations ◽  
Dual Mechanism

ABSTRACTThe majority of the human genome is made of transposable elements, giving rise to interspaced repeats, including Long Interspersed Element-1s (LINE-1s or L1s). L1s are active human DNA parasites involved in genomic diversity and evolution, but can also contribute to genomic instability and diseases. L1s require host factors to complete their life cycles, whereas the host has evolved numerous mechanisms to restrict L1-induced mutagenesis. Restriction mechanisms in somatic cells include methylation of the L1 promoter, anti-viral factors and RNA-mediated processes such as small RNAs. microRNAs (miRNAs or miRs) are small non-coding RNAs that post-transcriptionally repress multiple target genes often found in the same cellular pathways. We have recently established that the interferon-inducible miR-128 function as a novel restriction factor inhibiting L1 mobilization in somatic cells. We have further demonstrated that miR-128 function through a dual mechanism; by directly targeting L1 RNA for degradation and indirectly by inhibiting a cellular co-factor which L1 is dependent on to transpose to new genomic locations (TNPO1). Here we add another piece to the puzzle of the enigmatic L1 life cycle. We show that miR-128 also inhibits another key cellular factor, hnRNPA1, by significantly reducing mRNA and protein levels through direct interaction with the coding sequence (CDS) of hnRNPA1 mRNA. Furthermore, we demonstrate that repression of hnRNPA1 using shRNA significantly decreases de novo L1 retrotransposition and that induced hnRNPA1 expression enhances L1 mobilization. Finally, we determine that hnRNPA1 is a functional target of miR-128 and that induced hnRNPA1 expression in miR-128-overexpressing cells can partly rescue the miR-128-induced repression of L1’s ability to transpose to different genomic locations. Thus, we have identified an additional mechanism by which miR-128 represses L1 retrotransposition and mediate genomic stability.

scholarly journals Identification of three candidate mutations causing type IIA von Willebrand disease using a rapid, nonradioactive, allele-specific hybridization method

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 830-836 ◽  
Author(s):  
A Inbal ◽  
T Englender ◽  
N Kornbrot ◽  
AM Randi ◽  
G Castaman ◽  
...  
Keyword(s):  
De Novo ◽  
Screening Method ◽  
Von Willebrand Disease ◽  
Rapid Screening ◽  
De Novo Mutation ◽  
Platelet Glycoprotein ◽  
Missense Mutations ◽  
Hybridization Method ◽  
Allele Specific ◽  
Von Willebrand

Type IIA von Willebrand disease (vWD), the most common type II vWD variant, is characterized by decreased binding of von Willebrand factor (vWF) to platelet glycoprotein Ib (Gplb) and by a decrease in large and intermediate vWF multimers. Mutations reported to cause vWD type IIA are clustered within the A2 domain of vWF, which is encoded by exon 28. Genomic DNA from affected members of 12 unrelated families with type IIA vWD were screened for these mutations by a rapid, nonradioactive, allele-specific oligonucleotide (ASO) hybridization method. Oligonucleotides containing each of eight mutations were cross-linked onto a nylon membrane by UV irradiation. A fragment of vWF exon 28 was amplified from peripheral blood leukocyte DNA using biotinylated primers and hybridized to the immobilized oligonucleotides. Positive signals were detected with an avidin-alkaline phosphatase conjugate and chemiluminescent substrate. Thus, in a single hybridization reaction, a patient sample could be analyzed for a large number of mutations simultaneously. Polymerase chain reaction (PCR) products from four patients did not contain any of the tested mutations and therefore were sequenced. Three additional candidate missense mutations, two of them novel, were identified: Arg(834)-->Gln in one patient, Gly(846)-->Arg in one patient, and Val(902)-->Glu in three ostensibly unrelated patients. By ASO hybridization, the mutations were confirmed in the affected patients and excluded in unaffected relatives and 50 normal controls. In one family, the Val(902)-->Glu mutation was shown to be a de novo mutation. This rapid screening method is applicable to other subtypes of vWD for which mutations have been identified.

scholarly journals Structural analysis of de novo STXBP1 mutation in complex with syntaxin 1A reveals a major alteration in the interaction interface in a child with developmental delay and spasticity

2019 ◽  
Author(s):  
Ehud Banne ◽  
Tzipora Falik-Zaccai ◽  
Esther Brielle ◽  
Limor Kalfon ◽  
Hagay Ladany ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Direct Interaction ◽  
Md Simulations ◽  
Synaptic Function ◽  
Insertion Mutation ◽  
Coding Region ◽  
Syntaxin 1A ◽  
Diverse Range ◽  
And Function

AbstractSTXBP1, also known as Munc-18, is a master regulator of neurotransmitter release and synaptic function in the human brain through its direct interaction with syntaxin 1A. STXBP1 related disorders are well characterized and cover a diverse range of neurological and neurodevelopmental conditions. Through exome sequencing of a child with developmental delay, hypotonia and spasticity, we found a novel de novo insertion mutation of three nucleotides in the STXBP1 coding region, resulting in an additional arginine after position 39 (R39dup). Inconclusive results from state-of-the-art variant prediction tools mandated a structure-based approach using molecular dynamics (MD) simulations of the STXBP1-syntaxin 1A complex. Comparison of the interaction interfaces of the wild type and the R39dup complexes revealed a reduced interaction surface area in the mutant, leading to destabilization of the interaction. We applied the same MD methodology to 7 additional previously reported STXBP1 mutations. We find that the stability of the STXBP1-syntaxin 1A interface correlates with the reported clinical phenotypes. We illustrate a direct link between a patient’s genetic variations and the observed clinical phenotype through protein structure, dynamics, and function.

scholarly journals De novo macrocyclic peptides that specifically modulate Lys48-linked ubiquitin chains

2019 ◽  
Vol 11 (7) ◽  
pp. 644-652 ◽  
Author(s):  
Mickal Nawatha ◽  
Joseph M. Rogers ◽  
Steven M. Bonn ◽  
Ido Livneh ◽  
Betsegaw Lemma ◽  
...  
Keyword(s):  
De Novo ◽  
Macrocyclic Peptides

scholarly journals De-novo macrocyclic peptides dissect energy coupling of a heterodimeric ABC transporter by multimode allosteric inhibition

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Erich Stefan ◽  
Richard Obexer ◽  
Susanne Hofmann ◽  
Khanh Vu Huu ◽  
Yichao Huang ◽  
...  
Keyword(s):  
Abc Transporters ◽  
De Novo ◽  
Energy Coupling ◽  
Atp Binding ◽  
Inhibitory Effects ◽  
Conformational Switching ◽  
Substrate Transport ◽  
Physiological Processes ◽  
Macrocyclic Peptides ◽  
Transport Complex

ATP-binding cassette (ABC) transporters constitute the largest family of primary active transporters involved in a multitude of physiological processes and human diseases. Despite considerable efforts, it remains unclear how ABC transporters harness the chemical energy of ATP to drive substrate transport across cell membranes. Here, by random nonstandard peptide integrated discovery (RaPID), we leveraged combinatorial macrocyclic peptides that target a heterodimeric ABC transport complex and explore fundamental principles of the substrate translocation cycle. High-affinity peptidic macrocycles bind conformationally selective and display potent multimode inhibitory effects. The macrocycles block the transporter either before or after unidirectional substrate export along a single conformational switch induced by ATP binding. Our study reveals mechanistic principles of ATP binding, conformational switching, and energy transduction for substrate transport of ABC export systems. We highlight the potential of de novo macrocycles as effective inhibitors for membrane proteins implicated in multidrug resistance, providing avenues for the next-generation of pharmaceuticals.

scholarly journals De Novo Macrocyclic Peptide Inhibitors of Hepatitis B Virus Cellular Entry

2018 ◽  
Vol 25 (7) ◽  
pp. 906-915.e5 ◽  
Author(s):  
Toby Passioura ◽  
Koichi Watashi ◽  
Kento Fukano ◽  
Satomi Shimura ◽  
Wakana Saso ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
De Novo ◽  
Peptide Inhibitors ◽  
B Virus ◽  
Cellular Entry ◽  
Macrocyclic Peptide

scholarly journals Dose-dependent roles for canonical Wnt signalling in de novo crypt formation and cell cycle properties of the colonic epithelium

Development ◽  
2012 ◽  
Vol 140 (1) ◽  
pp. 66-75 ◽  
Author(s):  
A. Hirata ◽  
J. Utikal ◽  
S. Yamashita ◽  
H. Aoki ◽  
A. Watanabe ◽  
...  
Keyword(s):  
Cell Cycle ◽  
De Novo ◽  
Wnt Signalling ◽  
Colonic Epithelium ◽  
Canonical Wnt ◽  
Dose Dependent

Protein Docking and Drug Design

2018 ◽  
pp. 207-241
Author(s):  
Aditi Gangopadhyay ◽  
Hirak Jyoti Chakraborty ◽  
Abhijit Datta
Keyword(s):  
Drug Design ◽  
De Novo ◽  
Low Cost ◽  
Protein Docking ◽  
Rapid Screening ◽  
Structure Based Drug Design ◽  
Attrition Rates ◽  
Time Investment ◽  
Novel Drug ◽  
Druggable Targets

Protein docking is integral to structure-based drug design and molecular biology. The recent surge of big data in biology, the demand for personalised medicines, evolving pathogens and increasing lifestyle-associated risks, asks for smart, robust, low-cost and high-throughput drug design. Computer-aided drug design techniques allow rapid screening of ultra-large chemical libraries within minutes. This is immensely necessary to the drug discovery pipeline, which is presently burdened with high attrition rates, failures, huge capital and time investment. With increasing drug resistance and difficult druggable targets, there is a growing need for novel drug scaffolds which is partly satisfied by fragment based drug design and de novo methods. The chapter discusses various aspects of protein docking and emphasises on its application in drug design.

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