Structural and functional studies of small, disulfide-rich peptides depend on their efficient chemical synthesis folding. A large group derived from animals plants contains the Cys pattern C-C-CC-C-C that forms inhibitory cystine knot (ICK) or knottin motif. Here we report effect site-specific incorporation pairs selenocysteine residues oxidative folding activity omega-conotoxin GVIA, a well-characterized ICK-motif peptidic antagonist voltage-gated calcium channels. Three selenoconotoxin...

T-1-family conotoxins belong to the T-superfamily and are composed of 10−17 amino acids. They share a common cysteine framework disulfide connectivity exhibit unusual posttranslational modifications, such as tryptophan bromination, glutamic acid carboxylation, threonine glycosylation. We have isolated characterized novel peptide, Mo1274, containing 11 acids, that shows same pattern, -CC-CC, linkage those members. The complete sequence, GNWCCSARVCC, in which W denotes bromotryptophan, was...

Despite the therapeutic promise of disulfide-rich, peptidic natural products, their discovery and structure/function studies have been hampered by inefficient oxidative folding methods for synthesis. Here we report that converting three disulfide-bridged mu-conopeptide KIIIA into a disulfide-depleted selenoconopeptide (by removal noncritical disulfide bridge substitution disulfide- with diselenide-bridge) dramatically simplified its while preserving peptide's ability to block voltage-gated...

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused due to new coronavirus infection with 3716075 deaths across the world as reported by World Health Organization (WHO). SARS-CoV-2 main protease (Mpro) plays a vital role in replication of and thus attractive target for screening inhibitors therapy COVID-19. The preclinical drugs ebselen PX-12 are potent Mpro covalently modifies active site Cys-145 residue through selenosulfide/disulfide. In current report, using virtual...

The products of the Friedlander reaction, i.e., 1,8-naphthyridines, have far-reaching impacts in materials science, chemical biology, and medicine. reported synthetic methodologies elegantly orchestrate diverse routes naphthyridines but require harsh reaction conditions, organic solvents, expensive metal catalysts. Here, we introduce gram-scale synthesis 1,8-naphthyridines water using an inexpensive biocompatible ionic liquid (IL) as a catalyst. This is first-ever report on water. one-step...

Abstract Temporin-SHf is a linear, ultra-short, hydrophobic, α-helix, and phe-rich cationic antimicrobial peptide. The antitumor activities mechanism of temporin-SHf-induced cancer cell death are unknown. temporin-SHf was synthesized by solid-phase Fmoc chemistry were investigated. microbiocidal, non-hemolytic, cytotoxic to human cells but not non-tumorigenic cells. It affected the cells' lysosomal integrity caused membrane damage. inhibited A549 proliferation migration. anti-angiogenic...

Abstract The peptide library present in the venom of piscivorous marine snail Conus achatinus has been probed using a combination mass spectrometry and cDNA sequencing methods. Matrix assisted laser desorption ionization (MALDI‐MS) analysis, before following global reduction/alkylation mixtures, permits rapid classification individual components on basis number disulfide bonds. Mass fingerprinting reverse phase HPLC retention times permit further deconvolution terms size hydrophobicity....

Highly structured small peptides are the major toxic constituents of venom cone snails, a family widely distributed predatory marine molluscs. These animals use for rapid prey immobilization. The peptide components in target wide variety membrane‐bound ion channels and receptors. Many have been found to be highly selective diverse range mammalian receptors associated with pain‐signaling pathways. Their size, structural stability, specificity make them attractive pharmacologic agents. A...

Using molecular phylogeny has accelerated the discovery of peptidic ligands targeted to ion channels and receptors. One clade venomous cone snails, Asprella, appears be significantly enriched in conantokins, antagonists N-methyl d-aspartate receptors (NMDARs). Here, we describe characterization two novel conantokins from Conus rolani, including conantokin conRl-B that shown an unprecedented selectivity for blocking NMDARs contain NR2B subunits. ConRl-B shares only some sequence similarity...

Abstract Conformational diversity or “shapeshifting” in cyclic peptide natural products can, principle, confer a single molecular entity with the property of binding to multiple receptors. equilibria have been probed contryphans, which are peptides derived from Conus venom possessing 23‐membered disulfide moiety. The sequences inscriptus , GCV D LYPWC* (In936) and loroisii GCP WDPWC* (Lo959) differ number proline residues within macrocyclic ring. Structural characterisation distinct...

Disulfide crosslinks are ubiquitous in natural peptides and proteins, providing rigidity to polypeptide scaffolds. The assignment of disulfide connectivity multiple crosslinked systems is often difficult achieve. Here, we show that rapid unambiguous characterisation can be achieved through direct mass spectrometric CID fragmentation the intact polypeptides. method requires a native bonded polypeptides subsequent analysis using newly developed program, DisConnect. Technical difficulties...

Protein disulfide isomerase (PDI) has been identified in a protein extract from the venom duct of marine snail C. amadis. In-gel tryptic digestion thick band at approximately 55 kDa yields mixture peptides. Analysis fragments by MALDI-MS/MS and LC-ESI-MS/MS methods permits sequence assignment. Three yield two nine residue sequences (FVQDFLDGK 1 EPQLGDRVR 2) an eleven (DQESTGALAFK 3). Database analysis using peptides 3 were consistent with PDI peptide 2 appears to be derived co-migrating...

A multidisciplinary strategy for discovery of new Conus venom peptides combines molecular genetics and phylogenetics with peptide chemistry neuropharmacology. Here we describe application this approach to the conantokin family conopeptides targeting NMDA receptors. from rolani, ConRl-A, was identified using phylogeny subsequently synthesized functionally characterized. ConRl-A is a 24-residue containing three gamma-carboxyglutamic acid residues number unique sequence features compared...

Conotoxins comprise a large group of peptidic neurotoxins that use diverse disulfide-rich scaffolds. Each scaffold is determined by an evolutionarily conserved pattern cysteine residues. Although many structure-activity relationship studies confirm the functional and structural importance disulfide crosslinks, there growing evidence not all bridges are critical in maintaining activities conotoxins. To answer fundamental biological question what role noncritical is, we investigated function...

Abstract Objectives Based on previous screening results, the cytotoxic effect of hexane (JDH) and ethyl acetate extracts (JDE) marine sponge Jaspis diastra were evaluated HeLa cells present study aimed at determining their possible mechanism cell death. Methods Nuclear staining, membrane potential change, flow cytometry analysis cycle distribution annexin V staining undertaken to investigate effects JDE JDH. Electrospray ionization mass spectrometry (ESI-MS) nuclear magnetic resonance used...

Conformations of cysteine disulfides were analyzed in X-ray, nuclear magnetic resonance (NMR), and co-crystal structures peptide toxins retrieved from Protein Data Bank. The parameters side chain torsional angles, disulfide strain energy, interatomic Cα/Cβ distances, Ramachandran angles used as probes to derive conformational features disulfides. Schmidt, Ho, Hogg ( 2006 ) Allosteric bonds. Biochemistry, 45, 7429-7433 scheme was adapted classify the conformations toxins. Anomalies observed...