Machine learning designs new GCGR/GLP-1R dual agonists with enhanced biological potency.

Several peptide dual agonists of the human glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R) are in development for the treatment of type 2 diabetes, obesity and their associated complications. Candidates must have high potency at both receptors, but it is unclear whether the limited experimental data available can be used to train models that accurately predict the activity at both receptors of new peptide variants. Here we use peptide sequence data labelled with in vitro potency at human GCGR and GLP-1R to train several models, including a deep multi-task neural-network model using multiple loss optimization.

Systems Biology and Peptide Engineering to Overcome Absorption Barriers for Oral Peptide Delivery: Dosage Form Optimization Case Study Preceding Clinical Translation.

Oral delivery of peptides and biological molecules promises significant benefits to patients as an alternative to daily injections, but the development of these formulations is challenging due to their low bioavailability and high pharmacokinetic variability. Our earlier work focused on the discovery of MEDI7219, a stabilized, lipidated, glucagon-like peptide 1 agonist peptide, and the selection of sodium chenodeoxycholate (Na CDC) and propyl gallate (PG) as permeation enhancer combinations. We hereby describe the development of the MEDI7219 tablet formulations and composition optimization via in vivo studies in dogs.

Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease.

Peptide therapeutics are increasingly used in the treatment of disease, but their administration by injection reduces patient compliance and convenience, especially for chronic diseases. Thus, oral administration of a peptide therapeutic represents a significant advance in medicine, but is challenged by gastrointestinal instability and ineffective uptake into the circulation. Here, we have used glucagon-like peptide-1 (GLP-1) as a model peptide therapeutic for treating obesity-linked type 2 diabetes, a common chronic disease.

Targeted oral peptide delivery using multi-unit particulates: Drug and permeation enhancer layering approach.

Oral delivery of peptides is a challenge due to their instability and their limited transport and absorption characteristics within the gastrointestinal tract. In this work, we used layering techniques in a fluidized bed dryer to create a configuration in which the active peptide, permeation enhancers, and polymers are coated to control the release of the peptide. Formulations were developed to disintegrate at pH values of 5.

Affinity maturation of the RLIP76 Ral binding domain to inform the design of stapled peptides targeting the Ral GTPases.

Ral GTPases have been implicated as critical drivers of cell growth and metastasis in numerous Ras-driven cancers. We have previously reported stapled peptides, based on the Ral effector RLIP76, that can disrupt Ral signaling. Stapled peptides are short peptides that are locked into their bioactive form using a synthetic brace.

The discovery and maturation of peptide biologics targeting the small G-protein Cdc42: A bioblockade for Ras-driven signaling.

Aberrant Ras signaling drives 30% of cancers, and inhibition of the Rho family small GTPase signaling has been shown to combat Ras-driven cancers. Here, we present the discovery of a 16-mer cyclic peptide that binds to Cdc42 with nanomolar affinity. Affinity maturation of this sequence has produced a panel of derived candidates with increased affinity and modulated specificity for other closely-related small GTPases.

TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer's disease-associated H157Y variant.

We have characterised the proteolytic cleavage events responsible for the shedding of triggering receptor expressed on myeloid cells 2 (TREM2) from primary cultures of human macrophages, murine microglia and TREM2-expressing human embryonic kidney (HEK293) cells. In all cell types, a soluble 17 kDa N-terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and siRNA targeting ADAM10. Inhibitors of serine proteases and matrix metalloproteinases 2/9, and ADAM17 siRNA did not block TREM2 shedding.

Is more better? A comparison of tri- and tetrapeptidic catalysts.

From an enzymatic perspective, there is a general notion that the bigger and more complex a catalytically active peptide is the more enzyme-like and the better it should become. But is this really true? We have tackled this question firstly by screening split-and-mix-libraries of tri- and tetrapeptides for members that catalyze aldol reactions. Then, the catalytic performance of all possible diastereoisomers of related tri- and tetrapeptidic catalysts of the type H-Pro-Pro-Glu/Asp-NH and H-Pro-Pro-Glu/Asp-Pro-NH in aldol and conjugate addition reactions was compared.

Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC2 Agonism and Glucose-Dependent Insulin Secretion.

Agonists of vasoactive intestinal peptide receptor 2 (VPAC2) stimulate glucose-dependent insulin secretion, making them attractive candidates for the treatment of hyperglycaemia and type-II diabetes. Vasoactive intestinal peptide (VIP) is an endogenous peptide hormone that potently agonizes VPAC2. However, VIP has a short serum half-life and poor pharmacokinetics in vivo and is susceptible to proteolytic degradation, making its development as a therapeutic agent challenging.

Recombinant expression and in vitro characterisation of active Huwentoxin-IV.

Huwentoxin-IV (HwTx-IV) is a 35-residue neurotoxin peptide with potential application as a novel analgesic. It is a member of the inhibitory cystine knot (ICK) peptide family, characterised by a compact globular structure maintained by three intramolecular disulfide bonds. Here we describe a novel strategy for producing non-tagged, fully folded ICK-toxin in a bacterial system.

Potency optimization of Huwentoxin-IV on hNav1.7: a neurotoxin TTX-S sodium-channel antagonist from the venom of the Chinese bird-eating spider Selenocosmia huwena.

The spider venom peptide Huwentoxin-IV (HwTx-IV) 1 is a potent antagonist of hNav1.7 (IC50 determined herein as 17 ± 2 nM). Nav1.

Peptide catalyzed asymmetric conjugate addition reactions of aldehydes to nitroethylene--a convenient entry into gamma2-amino acids.

The peptide H-D-Pro-Pro-Glu-NH2 is a highly effective catalyst for conjugate addition reactions between aldehydes and nitroethylene. Only 1 mol % of H-d-Pro-Pro-Glu-NH2 and a 1.5-fold excess of aldehyde with respect to nitroethylene suffice to obtain gamma-nitroaldehydes and, after reduction, monosubstituted gamma-nitroalcohols in excellent yields and optical purities.

Separating stereoisomers of di-, tri-, and tetrapeptides using capillary electrophoresis with contactless conductivity detection.

The separation and detection of small oligopeptides in CE with contactless conductivity detection were demonstrated. A strongly acidic separation buffer (0.5 M acetic acid) was employed in order to render the species cationic.

Peptidic catalysts developed by combinatorial screening methods.

In recent years, oligopeptides have been developed as efficient catalysts for a range of important organic reactions, including acylation, silylation, oxidation, ester hydrolysis and aldol reactions. With many peptidic catalysts, high yields and chiral induction can be achieved under mild reaction conditions. Discovery and optimization of these catalysts typically involves the testing of compound collections and is therefore strongly linked to advances in combinatorial screening methods.

Peptide-polyethylene glycol conjugates: synthesis and properties of peptides bearing a C-terminal polyethylene glycol chain.

The introduction of a polyethylene glycol chain has become a popular tool for increasing water solubility and bioavailability. Our interest in the development of catalytically active peptides and the selective recognition of peptides has led us to investigate strategies to increase the solubility of peptides in organic solvents. Specifically, we became interested in the introduction of solubilizing moieties at the C-terminus of two peptides.

Solid-supported and pegylated H-Pro-Pro-Asp-NHR as catalysts for asymmetric aldol reactions.

H-Pro-Pro-Asp-NH2 is a highly active and selective catalyst for asymmetric aldol reactions. Here, the versatility of H-Pro-Pro-Asp-NH2 has been further improved by immobilization on a solid support and functionalization with a short polyethylene glycol linker at the C-terminus. The development, synthesis, and the catalytic properties in aldol reactions of H-Pro-Pro-Asp-resin and H-Pro-Pro-Asp-Ahx-NH(CH2CH2O)3CH3 are described.

Increased structural complexity leads to higher activity: peptides as efficient and versatile catalysts for asymmetric aldol reactions.

[reaction: see text] Peptides containing a secondary amine and a carboxylic acid in a specific orientation to each other are presented as highly efficient catalysts for asymmetric aldol reactions: (1) their activity is considerably higher compared to that of proline, and (2) the enantioselectivity of the peptidic catalysts can be changed from (R)- to (S)-selectivity by simple modifications of the secondary structure.

PS-COD and PS-9-BBN: polymer-supported reagents for solution-phase parallel synthesis.

1,5-Cyclooctadiene was deprotonated under LICKOR conditions and reacted with Merrifield resin to afford an immobilized cyclooctadiene in high yield. This polymer is effective as a halogen scavenger, while hydroboration leads to a supported 9-BBN analogue. The latter exhibits similar regioselectivity to 9-BBN in olefin hydroboration.

A 'triflate-like' tetrafluoroarylsulfonate linker for multifunctional solid-phase organic synthesis.

An arylsulfonate solid-phase linker is suitable for 'traceless' synthesis and Pd(0) catalyzed cross-coupling reactions.

Ionic liquid acceleration of solid-phase suzuki-miyaura cross-coupling reactions.

[reaction: see text] Room-temperature ionic liquids promote various transition metal-catalyzed reactions in the solution phase. Here, for the first time, we show that these effects are translatable to solid-phase reactions. The Suzuki-Miyaura cross-coupling of 4-iodophenol immobilized on polystyrene-Wang resin with various arylboronic acids was significantly accelerated by the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)(-)]).

Synthesis of functionalized 1,5-cyclooctadienes by LICKOR metalation.

1,5-Cyclooctadiene was lithiated under LICKOR superbase conditions followed by reaction with alkyl halides or ethylene oxide to yield 3-substituted 1,5-cyclooctadienes in high yield and purity. This procedure is suitable for preparation of 1,5-cyclooctadienes carrying pendant functional groups for immobilization on solid-phase resins.