Natural Bridged Bicyclic Peptide Macrobiomolecules from Celosia argentea and Amanita phalloides.

Bridged peptide macrobicycles (BPMs) from natural resources belong to types of compounds that are not investigated fully in terms of their formation, pharmacological potential, and stereo- chemical properties. This division of biologically active congeners with multiple circular rings has merits over other varieties of peptide molecules. BPMs form one of the most hopeful grounds for the establishment of drugs because of their close resemblance and biocompatibility with proteins, and these bio-actives are debated as feasible, realistic tools in diverse biomedical applications. Despite huge potential, poor metabolic stability and cell permeability limit the therapeutic success of macrocyclic peptides. In this review, we have comprehensively explored major bicyclic peptides sourced from plants and mushrooms, including ßs-leucyl-tryptophano-histidine bridged and tryptophanocysteine bridged peptide macrobicycles. The unique structural features, structure-activity relationship, synthetic routes, bioproperties, and therapeutic potential of the natural BPMs are also discussed.

Towards the Synthesis of a Heterocyclic Analogue of Natural Cyclooligopeptide with Improved Bio-properties.

AIMS: The present investigation is targeted towards the synthesis of a novel analogue of a natural peptide of marine origin. BACKGROUND: Marine sponges are enriched with bioactive secondary metabolites, especially circu-lar peptides. Heterocycles are established organic compounds with potential biological value. Tak-ing into consideration the bio-properties of heterocycles and marine sponge-derived natural pep-tides, an effort was made for the synthesis of a heterocyclic analogue of a natural cyclopeptide. OBJECTIVE: A heterocyclic analogue of a sponge-derived proline-containing cyclic peptide, rolloam-ide A, was synthesized by interaction of Boc-protected L-histidinyl-L-prolyl-L-valine and L-prolyl-L-leucyl-L-prolyl-L-isoleucine methyl ester and compared with synthetic rolloamide A with bioac-tivity against bacteria, fungi, and earthworms. METHODS: The synthesis of cycloheptapeptide was accomplished employing the liquid phase method. The larger peptide segment was prepared by interaction of Boc-protected L-prolyl-L-leu-cine with L-prolyl-L-isoleucine methyl ester. Similarly, the tripeptide unit was synthesized from Boc-protected L-histidinyl-L-proline with L-valine ester. The linear heptapeptide segment (7) was cyclized by utilizing pentafluorophenyl (pfp) ester, and the structure was elucidated by elemental and spectral (IR, 1H/13C NMR, MS) analysis. The peptide was also screened for diverse bioactivities such as antibacterial, antifungal, and potential against earthworms and cytotoxicity. RESULTS: The novel cyclooligopeptide was synthesized with 84% yield by making use of car-bodiimides. The synthesized cyclopeptide exhibited significant cytotoxicity against two cell lines. In addition, promising antifungal and antihelmintic properties were observed for newly synthesized heterocyclic peptide derivative (8) against dermatophytes and three earthworm species at 6 µg/mL and 2 mg/mL, respectively. CONCLUSION: Solution-phase technique employing carbodiimide chemistry was established to be promising for synthesizing the cycloheptapeptide derivative (8), and C5H5N was proved to be a better base for heptapeptide circling when compared to N-methylmorpholine and triethylamine.

Nanocarriers for Anticancer Drug Targeting: Recent Trends and Challenges.

Nanocarriers are nanostructured vehicles employed to deliver anticancer drugs to the targeted tumor sites in the body. Nanocarriers have been successfully employed to circumvent certain limitations of conventional anticancer drug delivery while providing greater bioavailability, prolonged circulation time and higher tumor accumulation for enhanced therapeutic outcomes in cancer treatment. Nanocarriers are also responsive to functionalization to tailor their pharmaco-kinetics and achieve enhanced therapeutic outcomes in cancer therapy. Among organic, inorganic and hybrid type, several nanocarriers have gained approval for use in cancer patients, while many more are under clinical development. For the last two decades, cancer immunotherapy-based advanced targeting approaches such as monoclonal antibodies, antibody drug conjugates and immune checkpoint inhibitors that utilize human immune system functions have vastly developed which furnish better treatment options in several intractable cancers compared with traditional cancer therapies. This review discusses the imperative role of tumor vasculature in passive and active targeting of anticancer drugs using organic and inorganic nanocarriers and the current research efforts underway. The advanced targeting approaches for treatment of various cancers and their most recent clinical development scenario have been comprehensively explored. Further, potential challenges associated with each type of nanocarrier, and their translational obstacles are addressed.

Natural Thiazoline-Based Cyclodepsipeptides from Marine Cyanobacteria: Chemistry, Bioefficiency and Clinical Aspects.

BACKGROUND: Peptides and peptide-based therapeutics are biomolecules that demarcate a significant chemical space to bridge small molecules with biological therapeutics, such as antibodies, recombinant proteins, and protein domains. INTRODUCTION: Cyclooligopeptides and depsipeptides, particularly cyanobacteria-derived thiazoline-based polypeptides (CTBCs), exhibit a wide array of pharmacological activities due to their unique structural features and interesting bioactions, which furnish them as promising leads for drug discovery. METHODS: In the present study, we comprehensively review the natural sources, distinguishing chemistries, and pertinent bioprofiles of CTBCs. We analyze their structural peculiarities counting the mode of actions for biological portrayals which render CTBCs as indispensable sources for emergence of prospective peptide-based therapeutics. In this milieu, metal organic frameworks and their biomedical applications are also briefly discussed. To boot, the challenges, approaches, and clinical status of peptide-based therapeutics are conferred. RESULTS: Based on these analyses, CTBCs can be appraised as ideal drug targets that have always remained a challenge for traditional small molecules, like those involved in protein- protein interactions or to be developed as potential cancer-targeting nanomaterials. Cyclization-induced reduced conformational freedom of these cyclooligopeptides contribute to improved metabolic stability and binding affinity to their molecular targets. Clinical success of several cyclic peptides provokes the large library-screening and synthesis of natural product-like cyclic peptides to address the unmet medical needs. CONCLUSION: CTBCs can be considered as the most promising lead compounds for drug discovery. Adopting the amalgamation of advanced biological and biopharmaceutical strategies might endure these cyclopeptides to be prospective biomolecules for futuristic therapeutic applications in the coming times.

A comprehensive review of chemistry and pharmacological aspects of natural cyanobacterial azoline-based circular and linear oligopeptides.

The cyanobacterial oligopeptides are recognized for being highly selective, efficacious and relatively safer compounds with diverse bioactivities. Azoline-based natural compounds consist of heterocycles which are reduced analogues of five-membered heterocyclic azoles. Among other varieties of azoline-based natural compounds, the heteropeptides bearing oxazoline or thiazoline heterocycles possess intrinsic structural properties with captivating pharmacological profiles, representing excellent templates for the design of novel therapeutics. The specificity of heteropeptides has been translated into prominent safety, tolerability, and efficacy profiles in humans. These peptidic congeners serve as ideal intermediary between small molecules and biopharmaceuticals based on their typically low production complexity compared to the protein-based biopharmaceuticals. The distinct bioproperties and unique structures render these heteropeptides one of the most promising lead compounds for drug discovery. The high degree of chemical diversity in cyanobacterial secondary metabolites may constitute a prolific source of new entities leading to the development of new pharmaceuticals. This review focuses on the azoline-based natural oligopeptides with emphasis on distinctive structural features, stereochemical aspects, biological activities, structure activity relationship, synthetic and biosynthetic aspects as well as mode of action of cyanobacteria-derived peptides.

Natural bioeffective cyclooligopeptides from plant seeds of Annona genus.

The Annona L. is one of the most significant genus of the Annonaceae family due to its widespread medicinal properties. This genus has a variety of active metabolites, including alkaloids, isoquinolines, peptides, acetogenins, lectins, volatile oils etc. Due to the constitution of cyclopeptides with an expanded spectrum of distinctive bioproperties, this genus is predominantly preferred over other species. The cytotoxicity, vasorelaxant activity, anti-inflammatory and other properties exhibited by cyclooligopeptides from seeds of Annona genus plants make these metabolites attractive leads for the drug discovery process. The present review covers the structural characteristics, structure activity relationship, synthesis strategies, pharmacological properties of plant seeds-originated bioactive peptides from Annona genus, which may be vital for the development of novel therapeutics based on peptide skeleton.

Natural cyclic polypeptides as vital phytochemical constituents from seeds of selected medicinal plants.

Cyclopolypeptides are among the most predominant biomolecules in nature, especially those derived from plant seeds. This category of compounds has gained extraordinary attention due to remarkable variety of structures and valuable biofunctions. These congeners display enormous variation in terms of both structure and function and are the most significant biomolecules due to their widespread bioproperties. The estrogenic activity, immunosuppressive activity, cytotoxicity, vasorelaxant activity, and other properties possessed by cyclic peptides from seeds of plants make these congeners attractive leads for the drug discovery process. The current study covers the important structural features, structure-activity relationship, synthesis methods, and bioproperties of plant seeds-originated bioactive peptides from Vaccaria segetalis, Linum usitatissimum, and Goniothalamus leiocarpus, which may prove vital for the development of novel therapeutics based on a peptide skeleton.

Natural Bioactive Thiazole-Based Peptides from Marine Resources: Structural and Pharmacological Aspects.

Peptides are distinctive biomacromolecules that demonstrate potential cytotoxicity and diversified bioactivities against a variety of microorganisms including bacteria, mycobacteria, and fungi via their unique mechanisms of action. Among broad-ranging pharmacologically active peptides, natural marine-originated thiazole-based oligopeptides possess peculiar structural features along with a wide spectrum of exceptional and potent bioproperties. Because of their complex nature and size divergence, thiazole-based peptides (TBPs) bestow a pivotal chemical platform in drug discovery processes to generate competent scaffolds for regulating allosteric binding sites and peptide-peptide interactions. The present study dissertates on the natural reservoirs and exclusive structural components of marine-originated TBPs, with a special focus on their most pertinent pharmacological profiles, which may impart vital resources for the development of novel peptide-based therapeutic agents.

Combinational effect of angiotensin receptor blocker and folic acid therapy on uric acid and creatinine level in hyperhomocysteinemia-associated hypertension.

Homocysteine [HSCH2 CH2 CH(NH2 )COOH] (Hcy) is a sulfur-containing amino acid of 135.18 Da of molecular weight, generated during conversion of methionine to cysteine. If there is a higher accumulation of Hcy in the blood, that is usually above 15 µmol/L, it leads to a condition referred to as hyperhomocysteinemia. A meta-analysis of observational study suggested an elevated concentration of Hcy in blood, which is termed as the risk factors leading to ischemic heart disease and stroke. Further experimental studies stated that Hcy can lead to an increase in the proliferation of vascular smooth muscle cells and functional impairment of endothelial cells. The analyses confirmed some of the predictors for Hcy presence, such as serum uric acid (UA), systolic blood pressure, and hematocrit. However, angiotensin-converting enzyme inhibitors angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) alone are inadequate for controlling UA and creatinine level, although the addition of folic acid may be beneficial in hypertensive patients who are known to have a high prevalence of elevated Hcy. We hypothesized that combination therapy with an ARB (olmesartan) and folic acid is a promising treatment for lowering the UA and creatinine level in hyperhomocysteinemia-associated hypertension.

A contemporary biological pathway of islet amyloid polypeptide for the management of diabetic dementia.

Major challenges of dealing elder patients with diabetes mellitus (DM) are the individualization of consideration in persons with various comorbid types of conditions. In spite of the fact that microvascular and macrovascular problems associated with DM are well documented, there is only a few numbers of reports viewing different conditions, for example, cognitive dysfunction. Cognitive dysfunction is of specific significance due to its effect on self-care and quality of life. All in all, the etiology of cognitive dysfunction in the maturing populace is probably going to be the grouping of ischemic and degenerative pathology. It is likewise trusted that Hyperglycemia is engaged with the system of DM-related cognitive dysfunction. At present, it isn't certain in the case of enhancing glycemic control or utilizing therapeutic agents can enhance the risk of cognitive decay. Amylin was later characterized as an amyloidogenic peptide, confined from a beta cell tumor and called islet amyloid polypeptide (IAPP), and after that, amylin. Conversely, we investigate the beneficial role and hypothesizing the mechanism of amylin related expanding the level and activation of CGRP receptor to enhance the cognition declination amid diabetic dementia.

Inhibition of indoleamine 2,3-dioxygenase attenuates endotoxin-mediated tolerance in granulosa cells through kynurenine pathway.

Ovarian granulosa cells (GCs) have been shown to have innate immune capabilities, which modulate their native endocrine functions through toll-like receptors (TLRs). We have recently shown that GCs exposed to lipopolysaccharide (LPS; 1.0 µg/mL) transiently regulate proinflammatory cytokine expression (interleukin 1ß [IL-1ß], IL-6, and tumor necrosis factor α) through chromatin remodeling. In the present study, we have demonstrated that GCs become tolerant to LPS on repeated exposure of LPS. To understand the mechanism of this endotoxin tolerance (ET) phenomenon in buffalo GCs, we have further studied the genome-wide transcriptomic analyses in buffalo GCs (unpublished data) and identified indoleamine 2,3-dioxygenase 1 (IDO1) gene, known to be involved in tryptophan catabolism, was found to be highly upregulated in endotoxin-tolerant GCs. Real-time gene expression analyses also showed similar results. Further analyses of tryptophan and tryptophan metabolite, kynurenine, showed that tryptophan was found to be depleted with the accumulation of kynurenine in the endotoxin-tolerant GCs. The effect of IDO1 induced ET was reversed when cells were pretreated with IDO1 inhibitor (1-methyl tryptophan, 1 mM). To the best of our knowledge, this is the first report describing the role of IDO1 gene in ET in GCs mimicked by repeated endotoxin exposure in vitro. In summary, the present study convincingly demonstrated that the tryptophan catabolism, through the kynurenine pathway, plays a crucial role as an immunomodulatory mechanism of ET in GCs. The finding could be exploited in developing potential therapeutics to treat impaired GCs function due to the ET underlying prolonged uterine or systemic infection leads to accumulation of endotoxin in follicular fluid.

Differentially expressed miRNA-210 during follicular-luteal transition regulates pre-ovulatory granulosa cell function targeting HRas and EFNA3.

Ovarian folliculogenesis, ovulation, and luteinization are an important prerequisite for fertility performance in mammals. Spatial and temporal key factors and proteins for their regulation are well known. Recent advancement in the field of molecular biology led to the discovery of another class of gene regulators, microRNA (miRNA). Previous studies on profiling of miRNA in buffalo ovaries revealed that miRNA-210 (miR-210) is differently expressed in follicular-luteal transition. Therefore, the present study was planned to ascertain the role of miR-210 in buffalo granulosa cells. Cultured granulosa cells were transfected with miR-210 mimic. Effect of overexpression of miR-210 was analyzed on granulosa cell marker genes (CYP19A1 and PCNA) which were significantly downregulated (P < 0.05). Further, target genes of miR-210 were screened using Target Scan software v7.1 and a list of 37 genes with cumulative weight context score (CWCS) > 0.5 was sorted followed by their functional annotation and network analyses using PANTHER and STRING software. Bioinformatics analyses identified HRas gene as a potential hub gene of miR-210 targeted genes. HRas has been shown to be involved in diverse biological pathways regulating ovarian functions. An expression analysis of HRas was further validated both in vitro and in vivo. EFNA3 (EFHRIN-A3), another identified target of miR-210 known to be involved in angiogenesis, was also downregulated in miR-210 transfected granulosa cells. In conclusion, the present study demonstrated that miR-210 can regulate granulosa cell function at preovulatory stage through HRas and EFNA3. Further studies are needed to find the mechanism how miR-210 regulates the granulosa cells function through these targets.