Seon-Yeong Kwak

Kojic acid-amino acid conjugates as tyrosinase inhibitors

Kojic acid (KA), a well known tyrosinase inhibitor, has insufficient inhibitory activity and stability. We modified KA with amino acids and screened their tyrosinase inhibitory activity. Among them, kojic acid-phenylalanine amide (KA-F-NH(2)) showed the strongest inhibitory activity, which was maintained for over 3 months at 50 degrees C, and acted as a noncompetitive inhibitor as determined by kinetic analysis. It also exhibited dopachrome reducing activity. We also propose a new tyrosinase inhibition mechanism based on the docking simulation data.

Synthesis and dual biological effects of hydroxycinnamoyl phenylalanyl/prolyl hydroxamic acid derivatives as tyrosinase inhibitor and antioxidant.

We previously reported that caffeoyl-amino acidyl-hydroxamic acid (CA-Xaa-NHOH) acted as both a good antioxidant and tyrosinase inhibitor, in particular when caffeic acid was conjugated with proline or amino acids having aromatic ring like phenylalanine. Here, various hydroxycinnamic acid (HCA) derivatives were further conjugated with phenylalanyl hydroxamic acid and prolyl hydroxamic acid (HCA-Phe-NHOH and HCA-Pro-NHOH) to study the structure and activity relationship as both antioxidants and tyrosinase inhibitors. When their biological activities were evaluated, all HCA-Phe-NHOH and HCA-Pro-NHOH exhibited enhanced antioxidant activity compared to HCA alone. Moreover, derivatives of caffeic acid, ferulic acid, and sinapic acid inhibited lipid peroxidation more efficiently than vitamin E analogue (Trolox). In addition, derivatives of caffeic acid and sinapic acid efficiently inhibited tyrosinase activity and reduced melanin content in melanocytes Mel-Ab cell.

Synergistic antioxidative activities of hydroxycinnamoyl‐peptides

Antioxidants have become an important subject of study as an active ingredient for cosmetics and preservatives for food. We synthesized antioxidative peptide conjugates of hydroxycinnamic acids (HCAs) such as ferulic acid (FA), caffeic acid (CA), and sinapic acid (SA) by SPPS method. We measured their potential antioxidant properties by 2,2‐diphenyl‐1‐picrylhydrazyl radical (DPPH) scavenging test and lipid autoxidation inhibition test. When the antioxidative peptides, such as glutathione analogue (GS(Bzl)H) and carnosine (CAR), were conjugated to HCAs, their antioxidative activities were enhanced significantly. CA‐peptides exhibited the highest free radical scavenging activity by the DPPH test, and showed good antioxidative activity in the lipid autoxidation test. FA‐ and SA‐peptides showed excellent antioxidative activity in the lipid autoxidation test. Furthermore, we demonstrated a synergistic antioxidative activity of HCA‐peptide conjugates by comparing their antioxidative activity with that of a simple mixture of HCAs and the antioxidant peptides. Copyright

Dual effects of caffeoyl-amino acidyl-hydroxamic acid as an antioxidant and depigmenting agent.

Anti-aging and depigmentation have both been an important subject of study for skin disease and the cosmetic industry. Caffeic acid (CA) has shown synergistically enhanced antioxidant activity when conjugated with amino acids. Hydroxamic acid (NHOH) is a well-known metal chelator, potentially having both tyrosinase inhibitory activity and free radical scavenging activity. We prepared caffeoyl-amino acidyl-hydroxamic acid (CA-Xaa-NHOH) and found that caffeoyl-prolyl-hydroxamic acid (CA-Pro-NHOH) contained excellent antioxidant activity and tyrosinase inhibitory activity by various bioassay systems. Also, CA-Pro-NHOH showed mild melanogenesis inhibitory activity in Mel-Ab cells.

Enhanced cell permeability of kojic acid-phenylalanine amide with metal complex.

Kojic acid-phenylalanine amide (KA-F-NH(2)), which showed an excellent tyrosinase inhibitory activity, did not inhibit melanogenesis in melanocyte due to its low cell permeability. To enhance its cell permeability by increasing lipophilicity, we prepared metal coordination compounds of KA-F-NH(2) and characterized them by FT-IR and ICP analysis. The metal complex of KA-F-NH(2) inhibited mushroom tyrosinase activity as much as KA-F-NH(2) and reduced melanin contents in melanocyte efficiently.

Direct Identification of On-Bead Peptides Using Surface-Enhanced Raman Spectroscopic Barcoding System for High-Throughput Bioanalysis

Recently, preparation and screening of compound libraries remain one of the most challenging tasks in drug discovery, biomarker detection, and biomolecular profiling processes. So far, several distinct encoding/decoding methods such as chemical encoding, graphical encoding, and optical encoding have been reported to identify those libraries. In this paper, a simple and efficient surface-enhanced Raman spectroscopic (SERS) barcoding method using highly sensitive SERS nanoparticles (SERS ID) is presented. The 44 kinds of SERS IDs were able to generate simple codes and could possibly generate more than one million kinds of codes by incorporating combinations of different SERS IDs. The barcoding method exhibited high stability and reliability under bioassay conditions. The SERS ID encoding based screening platform can identify the peptide ligand on the bead and also quantify its binding affinity for specific protein. We believe that our SERS barcoding technology is a promising method in the screening of one-bead-one-compound (OBOC) libraries for drug discovery.

Kojic acid–amino acid amide metal complexes and their melanogenesis inhibitory activities

Tyrosinase plays a critical role in the early stages of the melanin synthetic pathway by catalyzing the oxidation of the substrate. Therefore, tyrosinase inhibitors have been intensively studied in both cosmetic and food industries to develop hypopigmentary agents and prevent enzymatic browning in food. Previously, we reported that kojic acid–amino acid amide (KA‐AA‐NH2) showed enhanced tyrosinase inhibitory activity compared with kojic acid alone, but this was not observed in a cell test because of poor cell permeability. To enhance cell permeability, we prepared copper and zinc complexes of KA‐AA‐NH2 and characterized them using FT‐IR spectroscopy, ESI‐MS spectrometry, and inductively coupled plasma analysis. We then showed that KA‐AA‐NH2 copper complexes exhibited melanogenesis inhibitory activity in Mel‐Ab cells. Copyright

Chemical modulation of bioactive compounds via oligopeptide or amino acid conjugation.

Conjugation of an oligopeptide or an amino acid to bioactive compounds is one of the simplest chemical modifications to modulate the biological functions of the compounds. Recently, numerous methods have been proposed for the modification of their properties, including the alteration of their chemical and physical properties, and of their original bioactivities. We review the current knowledge of the adaptability of oligopeptide or amino acid conjugation for modulating the biological activities of biomolecules.

Solid Phase Synthesis of an Analogue of Insulin, A0:R glargine, That Exhibits Decreased Mitogenic Activity

Numerous analogues of insulin have been prepared over the past three decades for use in diabetic therapy. However, only two long-acting insulins have been approved for clinical use. One is Levemir (Novo Nordisk) and the other is Lantus (Sanofi-Aventis). Glargine (commercial name: Lantus) is characterized by a substitution of Gly in place of Asn at the C terminus of the A-chain and addition of two Arg residues to the C terminus of the B-chain. Despite the clinical advantages of glargine, it is not without concern that its increased affinity for the IGF-1 receptor may correlate with increased mitogenic activity. Recently, a systematic study of modified analogues of glargine showed that placement of an extra Arg residue at the N terminus of the A-chain conferred improved insulin:IGF-1 receptor selectivity without significant loss of pharmacological profile. However, as it is difficult to prepare such an analogue in high yield by recombinant DNA methods, we undertook its chemical assembly by our refined solid phase synthesis method. We describe herein its chemical preparation and biological activity in both insulin receptor binding assays and DNA synthesis assays. The synthetic analogue, A0:R glargine, showed slightly reduced affinity for IR-B (twofold) compared to native insulin. In stimulating DNA synthesis, A0:R glargine was slightly less potent compared to insulin or glargine. This result ultimately confirms the previous report that A0:R glargine has a lower potency in mitogenic assays compared to glargine. This glargine analogue thus could be a potential lead compound for drug design and development for the treatment of diabetes.

Corrigendum: Direct Identification of On-Bead Peptides Using Surface-Enhanced Raman Spectroscopic Barcoding System for High-Throughput Bioanalysis

Recently, preparation and screening of compound libraries remain one of the most challenging tasks in drug discovery, biomarker detection, and biomolecular profiling processes. So far, several distinct encoding/decoding methods such as chemical encoding, graphical encoding, and optical encoding have been reported to identify those libraries. In this paper, a simple and efficient surface-enhanced Raman spectroscopic (SERS) barcoding method using highly sensitive SERS nanoparticles (SERS ID) is presented. The 44 kinds of SERS IDs were able to generate simple codes and could possibly generate more than one million kinds of codes by incorporating combinations of different SERS IDs. The barcoding method exhibited high stability and reliability under bioassay conditions. The SERS ID encoding based screening platform can identify the peptide ligand on the bead and also quantify its binding affinity for specific protein. We believe that our SERS barcoding technology is a promising method in the screening of one-bead-one-compound (OBOC) libraries for drug discovery.