Solution Phase Peptide Synthesis: The Case of Biphalin.

Solution-phase synthesis was the first developed and the only method for peptide synthesis until the solid phase peptide synthesis (SPPS) introduced by Merrifield revolutionized the way peptides and their analogs are prepared nowadays. However, some peptides because of their chemical structure cannot be synthesized by SPPS and the "old school" technique is still favorable to make them. Biphalin is a good example.

High-Performance Liquid Chromatographic Separation of Stereoisomers of -Methyl-Substituted Unusual Amino Acids Utilizing Ion Exchangers Based on Alkaloids.

Novel peptides based on common amino acid building blocks may serve as possible drug candidates; however, their flexible structures may require stabilization via the incorporation of conformational constraints. The insertion of unusual amino acids is a feasible option that may provide improved pharmacokinetic and pharmacodynamic properties of such peptide-type drugs. The stereochemical purity of these kinds of building blocks must be verified by an efficient separation technique, such as high-performance liquid chromatography.

Peptidomimetic inhibitors of the VEGF-A/NRP-1 complex obtained by modification of the C-terminal arginine.

Inhibitors of the interaction between Neuropilin-1 (NRP-1) and Vascular Endothelial Growth Factor-A (VEGF-A) hold significant promise as therapeutic and diagnostic agents directed against cancers overexpressing NRP-1. In our efforts in this field, a few series of strong and fairly stable peptide-like inhibitors of the general formula Lys(Har)-Xaa-Xaa-Arg have been previously discovered. In the current work, we focused on Lys(Har)-Dap/Dab-Pro-Arg sequence.

Applications of biaryl cyclization in the synthesis of cyclic enkephalin analogs with a highly restricted flexibility.

A series of 10 cyclic, biaryl analogs of enkephalin, with Tyr or Phe residues at positions 1 and 4, were synthesized according to the Miyaura borylation and Suzuki coupling methodology. Biaryl bridges formed by side chains of the two aromatic amino acid residues are of the meta-meta, meta-para, para-meta, and para-para configuration. Conformational properties of the peptides were studied by CD and NMR.

Moving out of CF -Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF ) Group.

The NK1 receptor (NK1R) is a molecular target for both approved and experimental drugs intended for a variety of conditions, including emesis, pain, and cancers. While contemplating modifications to the typical NK1R pharmacophore, we wondered whether the CF groups common for many NK1R ligands, could be replaced with some other moiety. Our attention was drawn by the SF group, and so we designed, synthesized, and tested ten novel SF -containing compounds for NK1R affinity.

Structure-activity relationship studies and biological properties evaluation of peptidic NRP-1 ligands: Investigation of N-terminal cysteine importance.

Neuropilin-1 (NRP-1) is a major co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2). It may also stimulate tumour growth and metastasis independently of VEGF-A. These functions make VEGF-A/NRP-1 complex formation and its inhibition of great interest, where NRP-1 is the target for which effective ligands are sought.

The influence of a synthetic growth hormone-releasing hormone analogue G11 and opioid peptide biphalin on selected fibroblasts parameters relevant to wound healing.

The treatment of hard-to-heal chronic wounds is still a major medical problem and an economic and social burden. In this work, we examine the proregenerative potential of two peptides, G11 (a trypsin-resistant analogue of growth hormone-releasing hormone [GHRH]) and biphalin (opioid peptide), and their combination in vitro on human fibroblasts (BJ). G11, biphalin and their combination exhibited no toxicity against BJ cells.

Gα-derived peptide binds the µ-opioid receptor.

Background: G protein-coupled receptors (GPCRs) transduce external stimuli into the cell by G proteins via an allosteric mechanism. Agonist binding to the receptor stimulates GDP/GTP exchange within the heterotrimeric G protein complex, whereas recent structures of GPCR-G protein complexes revealed that the H5, S1 and S2 domains of Gα are involved in binding the active receptor, earlier studies showed that a short peptide analog derived from the C-terminus (H5) of the G protein transducin (G) is sufficient to stabilize rhodopsin in an active form.

Methods: We have used Molecular Dynamics simulations along with biological evaluation by means of radio-ligand binding assay to study the interactions between Gα-derived peptide (G-peptide) and the µ-opioid receptor (µOR).

Scandium-44 Radiolabeled Peptide and Peptidomimetic Conjugates Targeting Neuropilin-1 Co-Receptor as Potential Tools for Cancer Diagnosis and Anti-Angiogenic Therapy.

Pathological angiogenesis, resulting from an imbalance between anti- and pro-angiogenic factors, plays a pivotal role in tumor growth, development and metastasis. The inhibition of the angiogenesis process by the VEGF/VEGFR-2/NRP-1 pathway raises interest in the search for such interaction inhibitors for the purpose of the early diagnosis and treatment of angiogenesis-dependent diseases. In this work we designed and tested peptide-based radiocompounds that selectively bind to the neuropilin-1 co-receptor and prevent the formation of the pro-angiogenic VEGF-A/NRP-1 complex.

In Vitro Biological Evaluation of Aprepitant Based Lu-Radioconjugates.

Currently, the search for promising NK1R-positive tumor-targeting radiopharmaceuticals based on the structure of small molecular antagonists of neurokinin-1 receptor can be observed. Following this trend, we continued our evaluation of aprepitant-based Lu-radioconjugates in terms of future oncological applications. For this purpose, three novel aprepitant homologues were synthesized to broaden the previously obtained derivative portfolio, functionalized with the DOTA chelator and labeled with Ga and Lu.

HPLC-PDA-ESI-HRMS-Based Profiling of Secondary Metabolites of Anatomical and Hairy Roots Treated with Drought and Cold Stress.

To cope with environmental harmful conditions, plant cells developed adaptive strategy that involves production of a wide variety of complex secondary metabolites. The spectrum and quantity of biosynthesized compounds in specific plant species is determined by its genotype, tissue, developmental and physiological stage and environmental factors. This phenomenon was used to exploit the potential of anatomical and hairy root cultures of to produce bioactive compounds.

Novel NK1R-Targeted Ga-/Lu-Radioconjugates with Potential Application against Glioblastoma Multiforme: Preliminary Exploration of Structure-Activity Relationships.

Locoregionally administered, NK1 receptor (NK1R) targeted radionuclide therapy is a promising strategy for the treatment of glioblastoma multiforme. So far, the radiopharmaceuticals used in this approach have been based on the endogenous agonist of NK1R, Substance P or on its close analogues. Herein, we used a well-known, small molecular NK1R antagonist, L732,138, as the basis for the radiopharmaceutical vector.

Synthesis, Physicochemical and Biological Study of Gallium-68- and Lutetium-177-Labeled VEGF-A/NRP-1 Complex Inhibitors Based on Peptide A7R and Branched Peptidomimetic.

Neuropilin-1 (NRP-1) is a surface receptor found on many types of cancer cells. The overexpression of NRP-1 and its interaction with vascular endothelial growth factor-165 (VEGF) are associated with tumor growth and metastasis. Therefore, compounds that block the VEGF/NRP-1 interaction represent a promising strategy to image and treat NRP-1-related pathologies.

Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores.

Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.

() Hairy Roots with Antigenotoxic and Anti-Photogenotoxic Activity.

Hairy root cultures are considered as a valuable source of bioactive phytoconstituents with expanding applicability for their production. In the present study, hairy root cultures of (), a traditional Southeast Asian medicinal plant, were established. The transformation with ATCC 15834 allowed to obtain 15 root lines.

The solid state VCD of a novel N-acylhydrazone trifluoroacetate.

A novel N-acylhydrazone with pharmaceutical importance was subject of structural and IR/VCD investigations in the solid state. In the crystal structure, dimers of anion-cation pairs are stabilized by H-bonding and ionic interactions. Some less common interaction types, like C=N···C-NH (σ-hole) interactions, hydrazone-aromatic interactions and dispersive contacts of the CF groups are also present in the crystal.

Biphalin-A Potent Opioid Agonist-As a Panacea for Opioid System-Dependent Pathophysiological Diseases?

Biphalin, one of the opioid agonists, is a dimeric analog of enkephalin with a high affinity for opioid receptors. Opioid receptors are widespread in the central nervous system and in peripheral neuronal and non-neuronal tissues. Hence, these receptors and their agonists, which play an important role in pain blocking, may also be involved in the regulation of other physiological functions.

A Phage Display-Identified Short Peptide Capable of Hydrolyzing Calcium Pyrophosphate Crystals-The Etiological Factor of Chondrocalcinosis.

Chondrocalcinosis is a metabolic disease caused by the presence of calcium pyrophosphate dihydrate crystals in the synovial fluid. The goal of our endeavor was to find out whether short peptides could be used as a dissolving factor for such crystals. In order to identify peptides able to dissolve crystals of calcium pyrophosphate, we screened through a random library of peptides using a phage display.

The role of drugs and selected dietary factors in cutaneous squamous cell carcinogenesis.

Cutaneous squamous cell carcinoma represents the second most common non-melanoma skin cancer and its incidence increases worldwide. This review provides an overview of selected exogenous risk factors for cutaneous squamous cell carcinoma, which include drugs (azathioprine, calcineurin inhibitors, hydrochlorothiazide, angiotensin-converting-enzyme inhibitors) and few dietary factors (fat meet, whole milk products, arsenic) to better understand squamous skin cancer etiopathogenesis. Ingredients such as leafy vegetables, nuts, fish, caffeine, niacin are preventive factors for cutaneous squamous cell cancer.

Enantioseparation of ß-amino acids by liquid chromatography using core-shell chiral stationary phases based on teicoplanin and teicoplanin aglycone.

Enantioseparation of nineteen ß-amino acids has been performed by liquid chromatography on chiral stationary phases based on native teicoplanin and teicoplanin aglycone covalently bonded to 2.7 µm superficially porous silica particles. Separations were carried out in unbuffered (water/methanol), buffered [aqueous triethylammonium acetate (TEAA)/methanol] reversed-phase (RP) mode, and in polar-ionic (TEAA containing acetonitrile/methanol) mobile phases.

The Role of VEGF Receptors as Molecular Target in Nuclear Medicine for Cancer Diagnosis and Combination Therapy.

One approach to anticancer treatment is targeted anti-angiogenic therapy (AAT) based on prevention of blood vessel formation around the developing cancer cells. It is known that vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFRs) play a pivotal role in angiogenesis process; hence, application of angiogenesis inhibitors can be an effective approach in anticancer combination therapeutic strategies. Currently, several types of molecules have been utilised in targeted VEGF/VEGFR anticancer therapy, including human VEGF ligands themselves and their derivatives, anti-VEGF or anti-VEGFR monoclonal antibodies, VEGF binding peptides and small molecular inhibitors of VEGFR tyrosine kinases.

Urea-Peptide Hybrids as VEGF-A/NRP-1 Complex Inhibitors with Improved Receptor Affinity and Biological Properties.

Neuropilin-1 (NRP-1), the major co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2), may also independently act with VEGF-A to stimulate tumour growth and metastasis. Therefore, there is great interest in compounds that can block VEGF-A165/NRP-1 interaction. Peptidomimetic type inhibitors represent a promising strategy in the treatment of NRP-1-related disorders.

Antiproliferative effects of [D-Pro2, D-Trp7,9]-Substance P and aprepitant on several cancer cell lines and their selectivity in comparison to normal cells.

A neuropeptide, Substance P (SP), has mitogenic action in many types of cancer cells mediated via the neurokinin-1 receptor (NK1R). Small molecular NK1R antagonists have been frequently shown to possess anticancer activity both in vivo and in vitro, but there are only a few papers on such activity regarding peptide antagonists. In order to extend the data on this class of compounds, we have compared the effects of a peptide antagonist, [D-Pro2, D-Trp7,9]-Substance P, and a small molecular antagonist, aprepitant on the proliferation of five cancer and three normal cell lines.

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity.

AA3266 is a hybrid compound consisting of opioid receptor agonist and neurokinin-1 receptor (NK1R) antagonist pharmacophores. It was designed with the desire to have an analgesic molecule with improved properties and auxiliary anticancer activity. Previously, the compound was found to exhibit high affinity for μ- and δ-opioid receptors, while moderate binding to NK1R.