Leveraging the Mukaiyama oxidation-reduction condensation reaction for on-resin aryl thio-esterification for bio-conjugation.

A room-temperature Mukaiyama oxidation-reduction condensation inspired thioesterification methodology has been developed to afford aryl C-terminal peptide thioesters on-resin. The conditions herein feature mild reactions compatible with all Fmoc-SPPS protocols offering direct access to this critical arylthioester scaffold. This one-pot synthesis to aryl-thioester functionalised peptides facilitates peptide/protein synthesis by native chemical ligation.

Chemical Modifications on the αvβ6 Integrin Targeting A20FMDV2 Peptide: A Review.

Integrin proteins have received a significant increase in attention in recent scientific endeavors. The current trend uses the pre-established knowledge that the arginyl-glycyl-aspartic acid (RGD) structural motif present in the A20FMDV2 peptide is highly selective for the integrin class αvβ6 which is overexpressed in many cancer types. This review will provide an extensive overview of the existing literature research to date to the best of our knowledge, highlighting significant improvements and drawbacks of structure-activity relationships (SAR) work undertaken, aiding future research to identify established SAR for an informed design of future A20FMDV2 mimetic inhibitors.

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.

Novel Fluorescently Labeled PACAP and VIP Highlight Differences between Peptide Internalization and Receptor Pharmacology.

The related peptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have diverse biological functions in peripheral tissues and the central nervous system. Therefore, these peptides and their three receptors represent potential drug targets for several conditions, including neurological and pain-related disorders. However, very little is known about how these peptides regulate their receptors through processes such as internalization.

Characterization of Antibodies against Receptor Activity-Modifying Protein 1 (RAMP1): A Cautionary Tale.

Calcitonin gene-related peptide (CGRP) is a key component of migraine pathophysiology, yielding effective migraine therapeutics. CGRP receptors contain a core accessory protein subunit: receptor activity-modifying protein 1 (RAMP1). Understanding of RAMP1 expression is incomplete, partly due to the challenges in identifying specific and validated antibody tools.

PAC, VPAC, and VPAC Receptor Expression in Rat and Human Trigeminal Ganglia: Characterization of PACAP-Responsive Receptor Antibodies.

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide expressed in the trigeminal ganglia (TG). The TG conducts nociceptive signals in the head and may play roles in migraine. PACAP infusion provokes headaches in healthy individuals and migraine-like attacks in patients; however, it is not clear whether targeting this system could be therapeutically efficacious.

Synthesis, Antibacterial Activity, and Nephrotoxicity of Polymyxin B Analogues Modified at Leu-7, d-Phe-6, and the N-Terminus Enabled by S-Lipidation.

With the post-antibiotic era rapidly approaching, many have turned their attention to developing new treatments, often by structural modification of existing antibiotics. Polymyxins, a family of lipopeptide antibiotics that are used as a last line of defense in the clinic, have recently developed resistance and exhibit significant nephrotoxicity issues. Using thiol-ene chemistry, the facile preparation of six unique S-lipidated building blocks was demonstrated and used to generate lipopeptide mimetics upon incorporation into solid-phase peptide synthesis (SPPS).

Lipidated Calcitonin Gene-Related Peptide (CGRP) Peptide Antagonists Retain CGRP Receptor Activity and Attenuate CGRP Action .

Signaling through calcitonin gene-related peptide (CGRP) receptors is associated with pain, migraine, and energy expenditure. Small molecule and monoclonal antibody CGRP receptor antagonists that block endogenous CGRP action are in clinical use as anti-migraine therapies. By comparison, the potential utility of peptide antagonists has received less attention due to suboptimal pharmacokinetic properties.

Characterisation of agonist signalling profiles and agonist-dependent antagonism at PACAP-responsive receptors: Implications for drug discovery.

Background And Purpose: The pituitary adenylate cyclase-activating peptide (PACAP) family is of clinical interest for the treatment of migraine. These peptides activate three different PACAP-responsive class B G protein-coupled receptors: the PAC , VPAC and VPAC receptors. The PAC receptor may be alternatively spliced, generating variants that can differ in their pharmacological or signalling profiles.

Pharmacological characterisation of mouse calcitonin and calcitonin receptor-like receptors reveals differences compared with human receptors.

Background And Purpose: The calcitonin (CT) receptor family is complex, comprising two receptors (the CT receptor [CTR] and the CTR-like receptor [CLR]), three accessory proteins (RAMPs) and multiple endogenous peptides. This family contains several important drug targets, including CGRP, which is targeted by migraine therapeutics. The pharmacology of this receptor family is poorly characterised in species other than rats and humans.

Amylin Analog Pramlintide Induces Migraine-like Attacks in Patients.

Objective: Migraine is a prevalent and disabling neurological disease. Its genesis is poorly understood, and there remains unmet clinical need. We aimed to identify mechanisms and thus novel therapeutic targets for migraine using human models of migraine and translational models in animals, with emphasis on amylin, a close relative of calcitonin gene-related peptide (CGRP).

Evolution of Peptide-Based Prostate-Specific Membrane Antigen (PSMA) Inhibitors: An Approach to Novel Prostate Cancer Therapeutics.

Background: Prostate cancer is one of the most common cancers worldwide, with approximately 1.1 million cases diagnosed annually. The rapid development of molecular imaging has facilitated greater structural understanding, which can help formulate novel combinations of therapeutic regimens and more accurate diagnosis, avoiding unnecessary prostate biopsies.

Antagonism of CGRP Signaling by Rimegepant at Two Receptors.

The "gepants" are a class of calcitonin gene-related peptide (CGRP) receptor antagonist molecules that have been developed for the prevention and treatment of migraine. Rimegepant is reported to act at the CGRP receptor, has good oral bioavailability, and has had positive clinical trial results. However, there is very little data available describing its receptor pharmacology.

Distinct Patterns of Internalization of Different Calcitonin Gene-Related Peptide Receptors.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is involved in the transmission of pain. Drugs targeting CGRP or a CGRP receptor are efficacious in the treatment of migraine. The canonical CGRP receptor is a complex of a G protein-coupled receptor, the calcitonin-like receptor (CLR), with an accessory protein, receptor activity-modifying protein 1 (RAMP1).

Molecular Mechanisms of Class B GPCR Activation: Insights from Adrenomedullin Receptors.

Adrenomedullin (AM) is a 52 amino acid peptide that plays a regulatory role in the vasculature. Receptors for AM comprise the class B G protein-coupled receptor, the calcitonin-like receptor (CLR), in complex with one of three receptor activity-modifying proteins (RAMPs). The C-terminus of AM is involved in binding to the extracellular domain of the receptor, while the N-terminus is proposed to interact with the juxtamembranous portion of the receptor to activate signaling.

Receptor Activity Modifying Proteins Have Limited Effects on the Class B G Protein-Coupled Receptor Calcitonin Receptor-Like Receptor Stalk.

The calcitonin receptor-like receptor (CLR) is a class B G protein-coupled receptor (GPCR) that forms the basis of three pharmacologically distinct receptors, the calcitonin gene-related peptide (CGRP) receptor, and two adrenomedullin (AM) receptors. These three receptors are created by CLR interacting with three receptor activity-modifying proteins (RAMPs). Class B GPCRs have an N-terminal extracellular domain (ECD) and transmembrane bundle that are both important for binding endogenous ligands.

Total Synthesis of the Highly N-Methylated Acetylene-Containing Anticancer Peptide Jahanyne.

The first total synthesis of the highly N-methylated acetylene-containing lipopeptide jahanyne, an apoptosis-inducing natural product from marine cyanobacteria, is reported. A late-stage solution-phase coupling enabled introduction of the C-terminal ketone pyrrolidine moiety. A modified Fmoc solid-phase synthesis strategy was adopted to effectively couple multiple sterically hindered N-methylated amino acids while suppressing epimerization.