Drugs in middle space
The challenge for middle space research is to design drug molecules in synthetically accessible forms, with physical properties that permit cell membrane penetration and oral bioavailability. Image reproduced from Med. Chem. Commun., 2012, 3, 344, with permission from The Royal Society of Chemistry.
Crafting precise multivalent architectures
Development of elaborate three-dimensional multivalent displays appended on natural or synthetic molecular scaffolds.
Emac – a comparative index for the assessment of macrocyclization efficiency
Based upon a critical analysis of macrocyclization reactions published over the last three years, a macrocyclization efficiency index, Emac, is proposed, which takes into account both yield and concentration, as a means of determining the true efficiency of a macrocyclization reaction.
Informatic strategies for the discovery of
polyketides and nonribosomal peptides
A modern challenge and opportunity exists for in the ability to link genomic and metabolomic data, using novel informatic methods to find new bioactive natural products.
Biochemical and biosynthetic preparation of natural product-like
cyclic peptide libraries
Natural product gene clusters are increasingly being used to compliment biochemical methods for production of cyclic peptide libraries.
Unfolded and macrocyclic ammonium derivatives of diterpenoids steviol and isosteviol having choline moieties. Synthesis and inhibitory activities toward acetylcholine- and butyrylcholinesterases
Derivatives of isosteviol and steviol possessing choline moieties have been synthesized and assayed for AchE and BchE inhibitory activity.
Synthesis of precursors and macrocycle analogs of aerucyclamides as anti-trypanosomal agents
Macrocycle analogs and key fragments of aerucyclamides were obtained and evaluated against Trypanosoma brucei brucei.
Bicycle synthesis through
peptide macrocyclization using aziridine aldehydes followed by late stage disulfide bond installation
We present a method that can be applied to generate medium-sized peptidomimetic macrocycles equipped with disulfide bonds.
2P2Ichem: focused chemical libraries dedicated to orthosteric modulation of
protein– protein interactions
Design of focused chemical libraries dedicated to protein–protein interaction targets.
Pseudopeptides with a centrally positioned
alkene-based disulphide bridge mimetic stimulate kallikrein-related peptidase 3 activity
First successful pseudopeptides of the KLK3-activating bicyclic peptide “C-4” are reported.
Inhibition of Ras–
effector interactions by cyclic peptides
Screening of a combinatorial library identified a cyclic peptide that inhibits K-Ras–effector interactions at submicromolar concentration.
Novel FK506 and FK520 analogues via mutasynthesis: mutasynthon scope and product characteristics
Novel FK506 and FK520 analogues were generated via biosynthetic engineering in order to generate analogue compounds with equal potency but improved pharmacological profiles compared to FK506.
Phage display libraries of differently sized bicyclic peptides
Loop length variability in bicyclic peptide libraries increased the diversity of the motifs found in affinity selections towards the tumor-associated protease uPA.
Synthesis and binding affinities for sst receptors of cyclic peptoid SRIF-mimetics
Synthesis of the first all-peptoid SRIF (Somatotropin Release-Inhibiting Factor) analogues and evaluation of their binding affinities for the five human somatostatin receptors (hsst1–5).
Optimizing PK properties of
cyclic peptides: the effect of side chain substitutions on permeability and clearance
The impact of side chain functionality on the pharmacokinetics of an orally bioavailable cyclic peptide scaffold is investigated.
The solid phase supported
peptide synthesis of analogues of the lantibiotic lactocin S
Four analogues of lactocin S, an antimicrobial lantibiotic peptide produced by Lactobacillus sakei L45, have been generated using solid phase peptide synthesis. These compounds show enhanced oxidative stability to atmospheric oxygen and provide information on structure–activity relationships.
Unprecedented inhibition of resistant
penicillin binding proteins by bis-2-oxoazetidinyl macrocycles
Bis-2-oxoazetidinyl macrocycles, obtained as unexpected products of RCM cyclizations, exhibit good activities against D,D-peptidase from Actinomadura R39 and revealed very promising activities against PBP2a from methicillin-resistant Staphylococcus aureus.
About this collection
MedChemComm is delighted to publish a collection of articles covering important findings and advances in the field of non-traditional drug molecules that occupy the ‘middle space’ between ‘Rule of 5’ compliant small molecules and biologicals.
The collection, guest edited by Drs Nick Terrett (Ensemble Therapeutics) and David Rees (Astex Pharmaceuticals), will include the design, synthesis, optimization, modelling, analysis and profiling of peptides, peptidomimetics, macrocycles, natural products, natural product mimetics, and any other molecule in range of approximately 500 to 3000 Daltons.
Articles in this collection will be added below as soon as possible after they are published.
Please return to this page frequently to see the collection grow.