Peptide design to control protein-protein interactions.

Targeting of protein-protein interactions has become of huge interest in every aspect of medicinal and biological sciences. The control of protein interactions selectively offers the opportunity to control biological processes while limiting off target effects. This interest has massively increased with the development of cryo-EM and protein structure prediction with tools such as RosettaFold and AlphaFold.

Screening herbal and natural product libraries to aid discovery of novel allosteric modulators of human P2X7.

 P2X7 is an emerging therapeutic target for several disorders and diseases due to its role in inflammatory signalling. This study aimed to exploit the unique chemical libraries of plants used in traditional medicinal practices to discover novel allosteric modulators from natural sources. We identified several compounds from the NCI Natural Product library as P2X7 antagonists including confertifolin and digallic acid (IC values 3.

Light-activated azobenzene peptide inhibitor of the PD-1/PD-L1 interaction.

Inhibiting the PD-1/PD-L1 protein-protein interaction is a key immunotherapy for cancer. Antibodies dominate the clinical space but are costly, with limited applicability and immune side effects. We developed a photo-controlled azobenzene peptide that selectively inhibits the PD-1/PD-L1 interaction when in the isomer only.

Borylation iridium catalysed C-H activation: a new concise route to duocarmycin derivatives.

The synthesis of the ethyl ester analogue of the ultrapotent antitumour antibiotic seco-duocarmycin SA has been achieved in eleven linear steps from commercially available starting materials. The DSA alkylation subunit can be made in ten linear steps from the same precursor. The route involves C-H activation at the equivalent of the C7 position on indole leading to a borylated intermediate 9 that is stable enough for peptide coupling reactions but can be easily converted to the free hydroxyl analogue.

Strategies for converting turn-motif and cyclic peptides to small molecules for targeting protein-protein interactions.

The development of small molecules that interact with protein-protein interactions is an ongoing challenge. Peptides offer a starting point in the drug discovery process for targeting protein-interactions due to their larger, more flexible structure and the structurally diverse properties that allow for a greater interaction with the protein. The techniques for rapidly identifying potent cyclic peptides and turn-motif peptides are highly effective, but this potential has not yet transferred to approved drug candidates.

peptide-directed ligand design complements experimental peptide-directed binding for protein-protein interaction modulator discovery.

Using the protein-protein interaction of Mcl-1/Noxa, two methods for efficient modulator discovery are directly compared. peptide-directed ligand design is evaluated against experimental peptide-directed binding, allowing for the discovery of two new inhibitors of Mcl-1/Noxa with cellular activity. peptide-directed ligand design demonstrates an hit rate of 80% (IC < 100 μM).

Peptide directed phthalocyanine-gold nanoparticles for selective photodynamic therapy of EGFR overexpressing cancers.

Gold nanoparticles, covalently functionalised with the photosensitiser C11Pc and PEG, were actively targeted towards epidermal growth factor receptor overexpressing cancers using the peptide FITC-βAAEYLRK. Selective phototoxicity was observed at nanomolar concentrations with minimal dark toxicity.

Insights into the Structure-Activity Relationship of Glycosides as Positive Allosteric Modulators Acting on P2X7 Receptors.

P2X7 is an important ligand-gated ion channel expressed in multiple immune cell populations. This study aimed to investigate the chemical requirements of triterpenoid glycosides within a new binding pocket to characterize the structure-activity relationship. A set of glycosides were screened for positive modulator activity at human P2X7 using a YO-PRO-1 dye uptake assay in HEK-293 cells stably expressing the wild-type human P2X7 variant (HEK-hP2X7 cells).

A small molecule drug conjugate (SMDC) of DUPA and a duocarmycin built on the solid phase.

In a proof-of-concept study, solid phase synthesis allowed the rapid generation of a small molecule drug conjugate in which the glutamate carboxypeptidase II (GCPII) targeting small molecule DUPA was conjugated to the alkylating subunit of the potent cytotoxin duocarmycin SA. The targeted SMDC contained a cathepsin B cleavable linker, which was shown to be active and selective against cathepsin B over-expressing and GCPII-expressing tumour cell lines.

A Peptide-Duocarmycin Conjugate Targeting the Thomsen-Friedenreich Antigen Has Potent and Selective Antitumor Activity.

Solid-phase synthesis allowed the rapid generation of a peptide-drug conjugate. A peptide targeting the Thomsen-Friedenreich antigen (TFα) was conjugated to the alkylating subunit of the potent cytotoxin duocarmycin SA. The compound, containing a cathepsin B cleavable linker, was shown to be active and selective against TFα expressing tumor cell lines.

Identification of selective protein-protein interaction inhibitors using efficient peptide-directed ligand design.

The development of protein-protein interaction (PPI) inhibitors with therapeutic value is of increasing importance as the first clinical agent has now been approved, but PPIs remain difficult targets for the development of small molecule ligands. This article describes a highly efficient approach to the development of inhibitors of the p53/DMX or DM2 interaction that involves the design of small molecules based upon a peptide/protein structure. The process for molecule design, starting from a virtual library of just over 1200 fragments, led to the eventual synthesis of twenty compounds, of which ten bound to either DM2, DMX or both in binding assays.

Rac1 plays a role in CXCL12 but not CCL3-induced chemotaxis and Rac1 GEF inhibitor NSC23766 has off target effects on CXCR4.

Cell migration towards a chemotactic stimulus relies on the re-arrangement of the cytoskeleton, which is triggered by activation of small G proteins RhoA, Rac1 and Cdc42, and leads to formation of lamellopodia and actin polymerisation amongst other effects. Here we show that Rac1 is important for CXCR4 induced chemotaxis but not for CCR1/CCR5 induced chemotaxis. For CXCL12-induced migration via CXCR4, breast cancer MCF-7 cells are reliant on Rac1, similarly to THP-1 monocytes and Jurkat T-cells.

Peptide-Directed Binding for the Discovery of Modulators of α-Helix-Mediated Protein-Protein Interactions: Proof-of-Concept Studies with the Apoptosis Regulator Mcl-1.

Targeting PPIs with small molecules can be challenging owing to large, hydrophobic binding surfaces. Herein, we describe a strategy that exploits selective α-helical PPIs, transferring these characteristics to small molecules. The proof of concept is demonstrated with the apoptosis regulator Mcl-1, commonly exploited by cancers to avoid cell death.

Small-Molecule and Peptide Inhibitors of the Pro-Survival Protein Mcl-1.

The ability of protein-protein interactions to regulate cellular processes in both beneficial and detrimental ways has made them obvious drug targets. The Bcl-2 family of proteins undergo a series of protein-protein interactions which regulate the intrinsic cell-death pathway. The pro-survival members of the Bcl-2 family, including Bcl-2, Bcl-xL , and Mcl-1, are commonly overexpressed in a number of human cancers.

Identification of Small-Molecule Inhibitors of the Antiapoptotic Protein Myeloid Cell Leukaemia-1 (Mcl-1).

Protein-protein interactions (PPIs) control many cellular processes in cancer and tumour growth. Of significant interest is the role PPIs play in regulating apoptosis. The overexpression of the antiapoptosis regulating Bcl-2 family of proteins is commonly observed in several cancers, leading to resistance towards both radiation and chemotherapies.

Syntheses of the fungal metabolites boletopsins 7, 11, and 12 from the Papua New Guinea medicinal mushroom Boletopsis sp.

Boletopsins 7 (1), 11 (2), and 12 (3) are p-terphenyl dibenzofuran compounds, isolated from the Papua New Guinean medicinal mushroom Boletopsis sp. The first syntheses of these fungal metabolites are reported, allowing for an investigation of their antibiotic activity. The key steps include sequential Suzuki-Miyaura couplings to rapidly form the p-terphenyl backbone and an Ullmann ether synthesis on a formate ester to create the dibenzofuran moiety.

Stereochemical assignment of the fungal metabolites pestalotiopsones D and E through enantiopure synthesis.

The pestalotiopsones are fungal metabolites isolated from an endophytic fungus Pestalotiopsis sp. found in the mangrove Rhizophora mucronata, used in traditional Chinese medicine to treat symptoms of dysentery. The absolute configurations of pestalotiopsones D (4) and E (5) were elucidated through total synthesis of both the R and S enantiomers, allowing for the assignment of the stereochemistry of the natural compounds as the (+)-S enantiomers.

First syntheses of the biologically active fungal metabolites pestalotiopsones A, B, C and F.

A synthetic approach accessing the pestalotiopsones, fungal chromones possessing a rare skeletal subtype, is reported for the first time. The synthesis of pestalotiopsone A (1) has been achieved in 7 linear steps (28%), from commercially available 3,5-dimethoxybenzoic acid and subsequently the first syntheses of pestalotiopsone B (2), C (3) and F (4) were performed utilising this chemistry. The key steps include a newly described homologation of a substituted benzoic acid to afford phenylacetate derivatives utilising Birch reductive alkylation conditions, a microwave mediated chromanone formation proceeding through an oxa-Michael cyclisation, and an IBX induced dehydrogenation to the desired chromone skeleton.