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Drug Discovery Today. Technologies

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https://www.readbyqxmd.com/read/29249241/constrained-cell-penetrating-peptides
#1
REVIEW
S A Bode, D W P M Löwik
In this review we provide an overview of recent developments in the field of cell penetrating peptides (CPPs) on research that aims to achieve better control over their transduction properties - one of the big challenges - by means of restraining them. Three different constraining strategies are presented: triggerable activation, backbone rigidification and macrocyclization. Each of these methods have their opportunities in gaining control over CPP activity and selectivity.
December 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29249240/recent-advances-in-the-synthesis-of-cyclic-pseudopeptides
#2
REVIEW
Serge Zaretsky, Andrei K Yudin
Constrained peptides pose tremendous value in drug discovery. For example, owing to their large surface areas, they offer novel ways at inhibiting protein-protein interactions. As this field has grown, it has become desirable to introduce non-peptidic functionality into these rings to enable differentiated structure activity relationships and improved pharmacokinetic properties. Recent advances in the synthesis of cyclic pseudopeptides include macrocyclization through cysteine alkylation, multicomponent reactions, decarboxylative couplings, and novel stapling chemistry...
December 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29249239/tools-to-investigate-the-ubiquitin-proteasome-system
#3
REVIEW
Yves Leestemaker, Huib Ovaa
Ubiquitin is a 76-amino acid regulatory protein involved in many important cellular processes. Ubiquitin can be attached to other proteins at either a lysine residue or to the N-terminus by the consecutive actions of E1, E2, and E3 enzymes. Ubiquitin can also be attached to itself, resulting in poly-ubiquitin chains. Ubiquitination affects substrate proteins in different ways, for example by resulting in degradation of the substrate protein by the 26S proteasome. Ubiquitination can be reversed by deubiquitinating enzymes, which either trim or remove ubiquitin chains from proteins...
December 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29249238/identification-of-nonstandard-macrocyclic-peptide-ligands-through-display-screening
#4
REVIEW
Rhys Dylan Taylor, Matias Rey-Carrizo, Toby Passioura, Hiroaki Suga
Techniques facilitating the synthesis and screening of very high diversity nonstandard macrocyclic peptide libraries have led to such compounds receiving increasing attention as potential drug candidates. Specifically, approaches which allow the use of non-proteinogenic amino acids are proving to be particularly effective, since they expand the accessible chemical space of the starting library and thus allow the identification of compounds with structural similarity to known drugs. This review focuses on mRNA display screening platforms for drug discovery and their combined use with genetic code reprogramming to identify novel macrocyclic peptides with high affinities for disease-related targets of interest...
December 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29249237/enzyme-catalyzed-peptide-cyclization
#5
REVIEW
Marcel Schmidt, Ana Toplak, Peter J L M Quaedflieg, Jan H van Maarseveen, Timo Nuijens
The recent advancement of peptide macrocycles as promising therapeutics creates a need for novel methodologies for their efficient synthesis and (large scale) production. Within this context, due to the favorable properties of biocatalysts, enzyme-mediated methodologies have gained great interest. Enzymes such as sortase A, butelase 1, peptiligase and omniligase-1 represent extremely powerful and valuable enzymatic tools for peptide ligation, since they can be applied to generate complex cyclic peptides with exquisite biological activity...
December 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29249236/editorial-for-the-special-issue-on-constrained-peptides
#6
EDITORIAL
Jan H van Maarseveen, Peter Timmerman
No abstract text is available yet for this article.
December 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29233267/discovery-and-development-of-sv2a-pet-tracers-potential-for-imaging-synaptic-density-and-clinical-applications
#7
REVIEW
Joel Mercier, Laurent Provins, Anne Valade
Imaging synaptic density in vivo has promise for numerous research and clinical applications in the diagnosis and treatment monitoring of neurodegenerative and psychiatric diseases. Recent developments in the field of PET, such as SV2A human imaging with the novel tracers UCB-A, UCB-H and UCB-J, may help in realizing this potential and bring significant benefit for the patients suffering from these diseases. This review provides an overview of the most recent progress in the field of SV2A PET imaging, its potential for use as a biomarker of synaptic density and the future development areas...
November 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29233266/inflammation-and-dna-damage-probing-pathways-to-cancer-and-neurodegeneration
#8
REVIEW
Mehran Makvandi, Mark A Sellmyer, Robert H Mach
Cancer and neurodegeneration represent two opposite ends of the biological spectrum but contain many common biological mechanisms. Two such mechanisms include the elevated levels of oxidative stress and DNA damage. In this brief review, we describe current approaches for imaging these biological pathways with the molecular imaging technique, Positron Emission Tomography (PET), and the potential of PET imaging studies to measure the efficacy of anticancer drugs and strategies for delaying the progression of neurodegenerative disorders...
November 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29233265/use-of-carbon-11-labelled-tool-compounds-in-support-of-drug-development
#9
REVIEW
Giulia Boscutti, Mickael Huiban, Jan Passchier
The pharmaceutical industry is facing key challenges to improve return on R&D investment. Positron emission tomography (PET), by itself or in combination with complementary technologies such as magnetic resonance imaging (MRI), provides a unique opportunity to confirm a candidate's ability to meet the so-called 'three pillars' of drug development. Positive confirmation provides confidence for go/no-go decision making at an early stage of the development process and enables informed clinical progression. Whereas fluorine-18 has probably gained wider use in the community, there are benefits to using carbon-11 given the greater flexibility the use of this isotope permits in adaptive clinical study design...
November 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29233264/imaging-the-glutamate-receptor-subtypes-much-achieved-and-still-much-to-do
#10
REVIEW
Stefan Gruber, Simon M Ametamey
Functional imaging of glutamate receptors using PET imaging modality can be used to study numerous CNS disorders and also to select appropriate doses of clinically relevant glutamate-receptor-targeting candidate drugs. Great strides have been made in developing PET imaging probes for the non-invasive detection of glutamate receptors in the brain. This review highlights recent progress made towards the development of glutamatergic PET imaging agents. Focus is placed on PET imaging probes that have been labelled with either carbon-11 or fluorine-18...
November 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29233263/discovery-of-pet-radiopharmaceuticals-at-the-academia-industry-interface
#11
REVIEW
Vadim Bernard-Gauthier, Thomas L Collier, Steven H Liang, Neil Vasdev
Project-specific collaborations between academia and pharmaceutical partners are a growing phenomenon within molecular imaging and in particular in the positron emission tomography (PET) radiopharmaceutical community. This cultural shift can be attributed in part to decreased public funding in academia in conjunction with the increased reliance on outsourcing of chemistry, radiochemistry, pharmacology and molecular imaging studies by the pharmaceutical industry. This account highlights some of our personal experiences working with industrial partners to develop new PET radiochemistry methodologies for drug discovery and neuro-PET research studies...
November 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29233262/medicinal-chemistry-strategies-for-pet-tracer-discovery
#12
REVIEW
José Ignacio Andrés, Mark Schmidt
The detection of gamma rays, resulting from decay of positron emitting isotopes, allows exquisitely sensitive detection of probes radiolabeled with such isotopes. These probes can be designed for high affinity binding to specific molecular targets and be used as tools in the early development of drugs, particularly for neuropsychiatric disorders. Availability of novel tracers requires dedicated resources and selection assays. Many of the selection assays are similar to those used for discovery of clinical compounds, although the distribution and clearance of target specific radioligands requires different in vitro and in vivo methods and new derivatives...
November 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29233261/in-vivo-molecular-imaging-tools-facilitate-drug-discovery
#13
EDITORIAL
Yves P Auberson
No abstract text is available yet for this article.
November 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29233297/ppi-inhibitor-and-stabilizer-development-in-human-diseases
#14
REVIEW
Jürgen Bosch
All processes in living organisms are regulated by, or at least influenced by, protein-protein interactions (PPI). Membrane proteins play a fundamental part in this class of interactions: by providing inter-cellular communication and sensing capabilities to the cell, they lead to downstream regulation signaling events. It is therefore not surprising that PPI modulators are of keen interest when developing drug-like molecules for a range of diseases and medical conditions. However, techniques for exploiting PPIs in meaningful ways have only recently become readily available...
June 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29233296/protein-protein-and-protein-chromatin-interactions-of-ledgf-p75-as-novel-drug-targets
#15
REVIEW
Jolien Blokken, Jan De Rijck, Frauke Christ, Zeger Debyser
Lens epithelium-derived growth factor p75 (LEDGF/p75), a transcriptional co-activator, plays an important role in tethering protein complexes to the chromatin. Through this tethering function LEDGF/p75 is implicated in a diverse set of human diseases including HIV infection and mixed lineage leukemia, an aggressive form of cancer with poor prognosis. Here we provide an overview of recent progress in resolving protein-protein and protein-chromatin interaction mechanisms of LEDGF/p75. This review will focus on two well-characterized domains, the PWWP domain and the integrase binding domain (IBD)...
June 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29233295/novel-approaches-to-targeting-brd4
#16
REVIEW
Olesya A Kharenko, Henrik C Hansen
Inhibition of bromo and extra-terminal (BET) bromodomains, including BRD4, has emerged as a new exciting epigenetic target for oncology, in particular. Recently, novel alternatives to the traditional use of reversible small molecules have emerged, including proteolytic targeting BET agents and irreversible binding inhibitors. These alternatives to reversible inhibitors may offer some advantage and can be used as tools to further decipher the underlying biology. Supportive pre-clinical data have these novel approaches bound for clinical development in the near future...
June 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29233294/the-keap1-nrf2-protein-protein-interaction-a-suitable-target-for-small-molecules
#17
REVIEW
Dieter Schmoll, Christian K Engel, Heiner Glombik
The transcription factor Nrf2 controls pathways involved in oxidative-stress defense and is a potential pharmacological target for the treatment of chronic diseases. Activators of Nrf2 that have undergone clinical development are reactive molecules that are either associated with safety issues or for which it is unclear if their pharmacological efficacy depends on the activation of Nrf2. Therefore, the clinical validity of Nrf2 activation is not yet proven. The activity of Nrf2 is inhibited by Keap1 via a protein-protein interaction...
June 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29233293/protein-protein-interactions
#18
EDITORIAL
Christian Ottmann
No abstract text is available yet for this article.
June 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28647091/phenotypic-screening-the-fast-track-to-novel-antibody-discovery
#19
REVIEW
Ralph R Minter, Alan M Sandercock, Steven J Rust
The majority of antibody therapeutics have been isolated from target-led drug discovery, where many years of target research preceded drug program initiation. However, as the search for validated targets becomes more challenging and target space becomes increasingly competitive, alternative strategies, such as phenotypic drug discovery, are gaining favour. This review highlights successful examples of antibody phenotypic screens that have led to clinical drug candidates. We also review the requirements for performing an effective antibody phenotypic screen, including antibody enrichment and target identification strategies...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28647090/natural-product-inspired-compound-collections-evolutionary-principle-chemical-synthesis-phenotypic-screening-and-target-identification
#20
REVIEW
Luca Laraia, Herbert Waldmann
Natural products have been an excellent and abundant source of therapeutics for many decades. To expand on their success, and explore areas of chemical space not covered by biosynthesis, the synthesis of natural product-inspired compound collections has emerged as a viable strategy. Herein we describe the principles behind biology-oriented synthesis and related approaches, the requirements for development of novel chemistry and how phenotypic screens are a very fruitful way to explore the bioactivity of compounds made using these approaches...
March 2017: Drug Discovery Today. Technologies
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