A Stable Dehydratase Complex Catalyzes the Formation of Dehydrated Amino Acids in a Class V Lanthipeptide.

Lanthipeptides are ribosomally synthesized and post-translationally modified peptides that bear the characteristic lanthionine (Lan) or methyllanthionine (MeLan) thioether linkages. (Me)Lan moieties bestow lanthipeptides with robust stability and diverse antimicrobial, anticancer, and antiallodynic activities. Installation of (Me)Lan requires dehydration of serine and threonine residues to 2,3-dehydroalanine (Dha) and ()-2,3-dehydrobutyrine (Dhb), respectively.

Total Synthesis of (-)-Cordycicadin D and 3,4-trans-Cordycicadins A and B: Entry to the 3,4-trans-Fused Cordycicadin Framework.

Cordycicadins A-D are four C polyketides, all containing a γ-lactone fused to a 10-membered lactone. The proposed biosynthetic pathway for the cordycicadins anticipates the formation of two more natural products which are unknown. We report the total synthesis of (-)-cordycicadin D and the two anticipated natural products 3,4-trans-cordycicadins A and B.

Thanatin and vinyl sulfide analogues as narrow spectrum antimicrobial peptides that synergise with polymyxin B.

Thanatin is a β-hairpin antimicrobial peptide cyclised by a single disulfide bond that has shown potent broad-spectrum activity towards bacterial and fungal pathogens. Towards Gram-negative species, thanatin acts both by forming trans-membranal pores and inhibiting outer membrane biogenesis by binding to LptA and blocking lipopolysaccharide (LPS) transport. Inspired by previous modifications of thanatin, an analogue was prepared which demonstrated potent but selective activity towards .

Synthesis of the Spirocyclic Imine Fragment of Portimines Using a γ-Hydroxymethyl-αβ-butenolide Dienophile in a Diastereoselective Diels-Alder Reaction.

The synthesis of the spirocyclic imine fragment of the portimine family of marine toxins has been achieved. A densely functionalized key lactone-ester intermediate was assembled via a highly diastereoselective Diels-Alder cycloaddition, involving a novel γ-hydroxymethyl-α,β-butenolide dienophile. A Stille coupling was employed to install the vinyl group.

-Substituted Iminothiolane (NIT): A Promising Strategy for Protecting Lysine Side Chains for Solid-Phase Peptide Chemistry.

In this study, we introduce -substituted iminothiolane (NIT) as a robust protecting group for lysine side chains. NIT is compatible with Fmoc-SPPS and can be efficiently removed under mild nucleophilic conditions. Notably, NIT offers enhanced hydrophilicity compared to traditional orthogonal lysine-protecting groups and does not undergo intramolecular migration.

Histidine-bridged cyclic peptide natural products: isolation, biosynthesis and synthetic studies.

The histidine bridge is a rare and often overlooked structural motif in macrocyclic peptide natural products, yet there are several examples in nature of cyclic peptides bearing this moiety that exhibit potent biological activity. These interesting compounds have been the focus of several studies reporting their isolation, biosynthesis and chemical synthesis over the last four decades. This review summarises the findings on the structure, biological activity and, where possible, proposed biosynthesis and progress towards the synthesis of histidine-bridged cyclic peptides.

Synthesis of the bicyclic butenolide core of pallamolide A: a biomimetic approach.

Pallamolide A is a 7,8--labdane terpenoid possessing a unique bicyclo[2.2.2]octane core and a spiro-butenolide moiety.

Use of a Cyclic α-Alkylidene-β-Diketone as a Cleavable Linker Strategy for Antibody-Drug Conjugates.

In the fast-evolving landscape of targeted cancer therapies, the revolutionary class of biotherapeutics known as antibody-drug conjugates (ADCs) are taking center stage. Most clinically approved ADCs utilize cleavable linkers to temporarily attach potent cytotoxic payloads to antibodies, allowing selective payload release under tumor-specific conditions. In this study, we explored the utilization of 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde), a cyclic β-diketone featuring an active alkylidene group, to develop a novel chemically labile linker.

The Antimicrobial Peptide Capitellacin: Chemical Synthesis of Analogues to Probe the Role of Disulphide Bridges and Their Replacement with Vinyl Sulphides.

Capitellacin () is a 20-residue antimicrobial β-hairpin, produced by the marine polychaeta (segmented worms) . Since its discovery in 2020, only very limited studies have been undertaken to understand capitellacin's structure-activity relationship (SAR). Using fast-flow Fmoc-SPPS, a focused library of capitellacin analogues was prepared to systematically study the influence of the two disulphide bridges on its structure and activity, and their replacement with a vinyl sulphide as a potential bioisostere.

Allenamides as a Powerful Tool to Incorporate Diversity: Thia-Michael Lipidation of Semisynthetic Peptides and Access to β-Keto Amides.

Lipopeptides are an important class of biomolecules for drug development. Compared with conventional acylation, a chemoselective lipidation strategy offers a more efficient strategy for late-stage structural derivatisation of a peptide scaffold. It provides access to chemically diverse compounds possessing intriguing and non-native moieties.

Late-Stage Desulfurization Enables Rapid and Efficient Solid-Phase Synthesis of Cathepsin-Cleavable Linkers for Antibody-Drug Conjugates.

The synthesis of linker-payloads is a critical step in developing antibody-drug conjugates (ADCs), a rapidly advancing therapeutic approach in oncology. The conventional method for synthesizing cathepsin B-labile dipeptide linkers, which are commonly used in ADC development, involves the solution-phase assembly of cathepsin B-sensitive dipeptides, followed by the installation of self-immolative -aminobenzyl carbonate to facilitate the attachment of potent cytotoxic payloads. However, this approach is often low yield and laborious, especially when extending the peptide chain with components like glutamic acid to improve mouse serum stability or charged amino acids or poly(ethylene glycol) moieties to enhance linker hydrophilicity.

Synthesis, Structure-Activity Relationship Study, Bioactivity, and Nephrotoxicity Evaluation of the Proposed Structure of the Cyclic Lipodepsipeptide Brevicidine B.

The brevicidines represent a novel class of nonribosomal antimicrobial peptides that possess remarkable potency and selectivity toward highly problematic and resistant Gram-negative pathogenic bacteria. A recently discovered member of the brevicidine family, coined brevicidine B (), comprises a single amino acid substitution (from d-Tyr to d-Phe) in the amino acid sequence of the linear moiety of brevicidine () and was reported to exhibit broader antimicrobial activity against both Gram-negative (MIC = 2-4 μgmL) and Gram-positive (MIC = 2-8 μgmL) pathogens. Encouraged by this, we herein report the first total synthesis of the proposed structure of brevicidine B (), building on our previously reported synthetic strategy to access brevicidine ().

Creating New Antifoulants Using the Tools and Tactics of Medicinal Chemistry.

The unwanted accumulation of marine micro- and macroorganisms such as algae and barnacles on submerged man-made structures and vessel hulls is a major challenge for any marine operation. Known as biofouling, this problem leads to reduced hydrodynamic efficiency, significantly increased fuel usage, microbially induced corrosion, and, if not managed appropriately, eventual loss of both performance and structural integrity. Ship hull biofouling in the international maritime transport network conservatively accounts for 0.

Crystal Structure of Inhibitor-Bound GII.4 Sydney 2012 Norovirus 3C-Like Protease.

Norovirus is the leading cause of viral gastroenteritis worldwide, and there are no approved vaccines or therapeutic treatments for chronic or severe norovirus infections. The structural characterisation of the norovirus protease and drug development has predominantly focused upon GI.1 noroviruses, despite most global outbreaks being caused by GII.

The (Mānuka)-Specific Nectar and Honey Compound 3,6,7-Trimethyllumazine (Lepteridine) That Inhibits Matrix Metalloproteinase 9 (MMP-9) Activity.

3,6,7-trimethyllumazine (Lepteridine™) is a newly discovered natural pteridine derivative unique to Mānuka () nectar and honey, with no previously reported biological activity. Pteridine derivative-based medicines, such as methotrexate, are used to treat auto-immune and inflammatory diseases, and Mānuka honey reportedly possesses anti-inflammatory properties and is used topically as a wound dressing. MMP-9 is a potential candidate protein target as it is upregulated in recalcitrant wounds and intestinal inflammation.

Harnessing the power of a photoinitiated thiol-ene "click" reaction for the efficient synthesis of -lipidated collagen model peptide amphiphiles.

A photoinitiated thiol-ene "click" reaction was used to synthesize -lipidated collagen model peptide amphiphiles. Use of 2-iminothiolane provided an epimerization-free thiol handle required for thiol-ene based incorporation of lipid moieties onto collagen-based peptide sequences. This approach not only led to improvements in the triple helical characteristics of the resulting collagen model peptides but also increased the aqueous solubility of the peptide amphiphiles.

On-Resin Conjugation of the Ruthenium Anticancer Agent Plecstatin-1 to Peptide Vectors.

Ruthenium piano-stool complexes have been explored for their anticancer activity and some promising compounds have been reported. Herein, we conjugated a derivative of plecstatin-1 to peptides in order to increase their cancer cell targeting ability. For this purpose, plecstatin-1 was modified at the arene ligand to introduce a functional amine handle (), which resulted in a compound that showed similar activity in an anticancer activity assay.

P Glutamine isosteres in the design of inhibitors of 3C/3CL protease of human viruses of the class.

Viral infections are one of the leading causes of acute morbidity in humans and much endeavour has been made by the synthetic community for the development of drugs to treat associated diseases. Peptide-based enzyme inhibitors, usually short sequences of three or four residues, are one of the classes of compounds currently under development for enhancement of their activity and pharmaceutical properties. This review reports the advances made in the design of inhibitors targeting the family of highly conserved viral proteases 3C/3CL, which play a key role in viral replication and present minimal homology with mammalian proteases.

NMR Shows Why a Small Chemical Change Almost Abolishes the Antimicrobial Activity of Glycocin F.

Glycocin F (GccF), a ribosomally synthesized, post-translationally modified peptide secreted by KW30, rapidly inhibits the growth of susceptible bacteria at nanomolar concentrations. Previous studies have highlighted structural features important for its activity and have shown the absolute requirement for the Ser18 -linked GlcNAc on the eight-residue loop linking the two short helices of the (C-X6-C) structure. Here, we show that an ostensibly very small chemical modification to Ser18, the substitution of the C proton with a methyl group, reduces the antimicrobial activity of GccF 1000-fold (IC 1.

Recent developments in the cleavage, functionalization, and conjugation of proteins and peptides at tyrosine residues.

Peptide and protein selective modification at tyrosine residues has become an exploding field of research as tyrosine constitutes a robust alternative to lysine and cysteine-targeted traditional peptide/protein modification protocols. This review offers a comprehensive summary of the latest advances in tyrosine-selective cleavage, functionalization, and conjugation of peptides and proteins from the past three years. This updated overview complements the extensive body of work on site-selective modification of peptides and proteins, which holds significant relevance across various disciplines, including chemical, biological, medical, and material sciences.

Expedient synthesis of imino-C-nucleoside fleximers featuring a one-pot procedure to prepare aryl triazoles.

Nucleoside analogues such as the antiviral agents galidesivir and ribavirin are of synthetic interest. This work reports a "one-pot" preparation of similar fleximers using a bifunctional copper catalyst that generates the aryl azide , which is captured by a terminal alkyne to effect triazole formation.