A Comprehensive Review on Therapeutic Potentials of Natural Cyclic Peptides

Cyclic peptides have emerged as a promising class of organic compounds that possess polypeptide chains with a cyclic ring structure. There is a circular sequence of bonds in which the ring structure is formed via linkage between one end of the peptide bond and the other end with an amide bond or any other chemically stable bonds like ether, thioether, lactone, and disulfide. Generally, the cyclic peptides are isolated from natural resources like invertebrate animals, micro-organisms of marine habitats, and higher plants. These cyclic peptides possess unique structures with diverse pharmacological activities. Now a day, cyclic peptides possess superior therapeutic value due to several reasons such as greater resistance to enzymatic degradation (in vivo) and higher bio-availability. Some of these cyclic peptides are rich in leucine, proline while some have other amino acids as their major constituents. Numerous novel cyclic peptides isolated from natural sources are successfully developed as bioactive products. Recently, cyclic peptides derived from natural resources have attracted attention for exploring their numerous beneficial effects. Moreover, it is reported that natural cyclic peptides exhibit various therapeutic activities like an anthelmintic, ACE inhibitor, anti-tumor, microtubule inhibitor, anti-fungal, anti-malarial, and platelet aggregation inhibiting activity. In this review, various cyclic peptides are reported with structures and biological activities that are isolated from various natural sources. The natural cyclic peptides possess a wide spectrum of biological activities and can become a drug of the future for replacing the existing drugs which develop resistance

Oral and Topical Anti-Inflammatory Activity of Jatropha integerrima Leaves Extract in Relation to Its Metabolite Profile

Jatropha integerrima Jacq., family: Euphorbiaceae, is used in India and subtropical Africa to treat different skin conditions. In this study we evaluated the anti-inflammatory activity of J. integerrima leaves extract (JILE) using rat paw edema model. The extract was administered orally (200 and 400 mg/kg) or applied topically as creams at 2.5, 5, and 10% strength. Four hours post-treatment, maximum reduction of edema volume by 63.09% was observed after oral administration of JILE (400 mg/kg) as compared to indomethacin with 60.43%. The extract anti-inflammatory effect was accompanied by a decrease in NO, prostaglandin PGE2, TNF-a and PKC levels by 19, 29.35, 16.9, and 47.83%, respectively. Additionally, topical applications of JILE showed dose dependent reduction in paw edema and resulted in normalized levels of PGE2, TNF-a, and PKC when used as 10% cream. Signs of inflammations were reduced or absent from paw tissue of animals receiving JILE either orally or topically. Finally, liquid chromatography/mass spectrometry analysis of JILE resulted in the annotation of 133 metabolites including 24 diterpenoids, 19 flavonoids, 10 phenolic acid conjugates, 8 cyclic peptides, 6 phytosterols, 4 sesquiterpenes, and 4 coumarins. Several of the annotated metabolites have known anti-inflammatory activity including vitexin, isovitexin, fraxitin, scopeltin, stigmasterol, and many diterpenoidal derivatives.

A new amino acid for improving permeability and solubility in macrocyclic peptides through side chain-to-backbone hydrogen bonding.

Despite the notoriously poor membrane permeability of peptides in general, many cyclic peptide natural products show high passive membrane permeability and potently inhibit a variety of “undruggable” intracellular targets. A major impediment to designing cyclic peptides with good permeability is the high desolvation energy associated with the peptide backbone amide NH groups. Strategies for mitigating the deleterious effect of the backbone NH group on permeability include N-methylation, steric occlusion, and the formation of intramolecular hydrogen bonds with backbone carbonyl oxygens, while there have been relatively few studies on the use of polar side chains to sequester backbone NH groups. We investigated the ability of N,N-pyrrolidinyl glutamine (Pye), whose side chain contains a powerful hydrogen bond accepting C=O amide group but no hydrogen bond donors, to sequester exposed backbone NH groups in a series of cyclic hexapeptide diastereomers. Analyses of partition coefficients, lipophilic permeability efficiencies (LPE), artificial and cell-based permeability assays revealed that specific Leu-to-Pye substitutions conferred dramatic improvements in aqueous solubility and permeability in a scaffold- and position-dependent manner. Introduction of the Pye residue thus offers a complementary tool, alongside traditional approaches, for improving membrane permeability and solubility in cyclic peptides.

Head-to-tail cyclization for synthesis of naturally occurring cyclic peptides on organophosphous small-molecular supports

To achieve the head-to-tail cyclic peptides via the liquid-phase on-support cyclization and synergistic self-cleavage strategy, 4,4’-bis(diphenylphosphinyloxyl) diphenyl ketoxime (BDKO) and 4-diphenyl phospholoxy benzyl alcohol (DPBA) were designed and prepared as...

Cyclic Peptides from the Soft Coral-Derived Fungus Aspergillus sclerotiorum SCSIO 41031

Three novel cyclic hexapeptides, sclerotides C–E (1–3), and a new lipodepsipeptide, scopularide I (4), together with a known cyclic hexapeptide sclerotide A (5), were isolated from fermented rice cultures of a soft coral-derived fungus: Aspergillus sclerotiorum SCSIO 41031. The structures of the new peptides were determined by 1D and 2D NMR spectroscopic analysis, Marfey’s method, ESIMS/MS analysis, and single crystal X-ray diffraction analysis. Scopularide I (4) exhibited acetylcholinesterase inhibitory activity with an IC50 value of 15.6 μM, and weak cytotoxicity against the human nasopharyngeal carcinoma cell line HONE-EBV with IC50 values of 10.1 μM.