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Fundamentals of Modern Peptide Synthesis
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
Clinical and preclinical studies of the therapeutic and proliferative effects of amino acids are ongoing (Meletis and Barker 2005). Vaccine studies are really important. There has been a growing interest in the field of synthetic peptide vaccines over the last decade due to numerous adverse effects of other vaccine models. Peptides are becoming popular in the vaccination industry due to their applications with better potency, high specificity, low toxicity, and natural availability. Various amino acid groups are used in the synthesis of peptide vaccines (Yang and Kim 2015) and therefore for developing new techniques to synthesize new amino acids with maximum benefits. Amino acids can be synthesized in three ways. The first is extraction of protein hydrolysates, the second is chemical synthesis of amino acids, and the third is using the microorganism enzymatic and fermentation route. Through these methods. fermentation is one of the safe and developing processes for the commercial production of amino acids because of the new genetic engineering applications that are maximizing the yield and fertility of amino acids (Ikeda 2003). Essentially, amino acids exist as L-enantiomers in all organisms. On the other hand, there are important amounts of D-amino acids forms that are manufactured by bacteria with fermentation (Bardaweel 2014). The importance of D-amino acids is that the bacteria are involved in the synthesis of amino acids and amino acids are cross-linked by peptidoglycan (Vollmer, Blanot, and de Pedro 2008).
Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
To explain the mechanism of action of penicillin, it is necessary to understand the structure of the bacterial cell wall. The cell wall is essential for bacteria to survive in a range of environments, such as varying pH, temperature, and osmotic pressure. The cell wall is composed of peptidoglycan; its structure consists of a parallel series of sugar backbones made of two types of sugar, namely N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG). Peptide chains are bound to the NAM sugars. The presence of D-amino acids in the chain is noteworthy because in humans, biochemistry only involves L-amino acids, which gives the opportunity for target selectivity. Bacteria have racemase enzymes that can convert L-amino acids to D-amino acids, required for biochemical uses such as cell wall synthesis. The cell wall is constructed with the peptide chains linked together by the displacement of D-alanine from one chain by glycine in another. This final cross-linking reaction is the one that is inhibited by penicillin. Consequently, the cell wall framework is no longer interlinked and is fragile; it does not stop the cell from swelling, which eventually bursts (lysis) and kills the bacterium. Different types of penicillin are used in this way to inhibit the transpeptidase enzyme responsible for cell wall construction for a range of bacteria. The severity of damage is greater for gram-positive bacteria, which have thicker cell walls, consisting of 50–100 peptidoglycan layers.
Single Amino Acids
Published in Luke R. Bucci, Nutrition Applied to Injury Rehabilitation and Sports Medicine, 2020
Studies on wound healing in animals made protein-deficient found that the impairment of healing caused by protein deficiency could be corrected almost to normal by administration of methionine or cysteine.308–312 Improved fibroblastic proliferation, reversal of prolonged lag phase, and collagen synthesis were found after repletion with methionine or cysteine. Sulfhydryl amino acids were suspected to be integral to collagen synthesis since it was known that cysteine disulfide bridges were critical for proper formation and maturation of newly synthesized procollagen. Now it is known that the important roles of sulfhydryl amino acids as antioxidants and precursors for glutathione may have accounted for some of the observed effects. However, a subsequent study did not find beneficial effects of methionine repletion on wound healing in protein-deficient rats.313 Additional supplies of methionine or cysteine did not enhance wound healing in animals with adequate intake or status of sulhydryl amino acids. These studies, performed in the 1950s, utilized D,L forms of amino acids (not nature-identical L forms). Thus, the known problems associated with administration of D amino acids may have obscured possible beneficial effects of sulfur-containing amino acids on enhancement of healing. At this point, the use of high doses of sulfur-containing amino acids as single agents to enhance wound healing is not supported, but conclusive research has not been performed.
Recent advances in proteolytic stability for peptide, protein, and antibody drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Xianyin Lai, Jason Tang, Mohamed E.H. ElSayed
High-molecular-weight MUC2 mucin glycoproteins are expressed in elevated levels of human colonic carcinoma. An epitope (18PTGTQ22) within the 1PTTTPITTTTTVTPTPTPTGTQT23 tandem-repeat unit of MUC2 glycoprotein is considered as synthetic vaccines in active specific immunotherapy to stimulate the B cell-specific immune responses of patients with MUC2 related disease. Eleven peptides with the sequence of 15TPTPTGTQTPT25 were produced containing the PTGTQ epitope and systematical substitution by one to three D-amino acids at C- and N-terminal regions. The peptides were incubated with human serum and rat liver lysosomal preparation. The results showed that the presence of D-amino acids only at the C terminus does not improve the degradation kinetics, the D-amino acid(s) present only at the N terminus improved the stability, and replacement simultaneously at both ends of the peptide lead to compounds with almost full protection against serum degradation [100]. Others also demonstrated that the replacement of D-amino acid residues in linear and multichain polypeptide antigens improved their stability to proteolysis [101].
Synergistic effects of D-arginine, D-methionine and D-histidine against Porphyromonas gingivalis biofilms
Published in Biofouling, 2021
Zhenyang Zhang, Baosheng Li, Qing Cai, Shuwei Qiao, Dan Wang, Heling Wang, Huiyan Zhang, Yalan Yang, Weiyan Meng
In recent decades, D-amino acids (D-AAs) have been found in microorganisms, plants, and humans (Friedman 2010). Especially in microorganisms, D-AAs are essential components of cell wall peptidoglycans, where they participate in the synthesis and assembly process as well as in the metabolism of bacteria. Subsequently, D-AAs were discovered during the biofilm lifecycle, that is, D-AAs were produced and accumulated rapidly in the dispersion phase (Kolodkin-Gal et al. 2010). Thereafter, several D-AAs were found to be effective in inhibiting biofilm formation of classic pathogenic bacteria (Kolodkin-Gal et al. 2010; Gnanadhas et al. 2015; Dawe et al. 2017). The present authors previously revealed that D-arginine, D-valine, and several other D-AAs had the ability to inhibit the formation of P. gingivalis biofilms and trigger the disassembly of mature P. gingivalis biofilms (Qi et al. 2018; Li et al. 2020). Considering the cytotoxic effects of D-AAs at certain concentrations (Bardaweel et al. 2013), finding an ideal strategy to combat biofilms while avoiding the cytotoxicity of D-AAs is potentially relevant. In addition, small molecules do not always show synergistic effects in treating diseases, independent or even antagonistic effects can occur (Iyer 2016).
D-Alanine Is Reduced by Ocular Hypertension in the Rat Retina
Published in Current Eye Research, 2020
Takashi Kanamoto, Hiroaki Sakaue, Yasushi Kitaoka, Ryo Asaoka, Kei Tobiume, Yoshiaki Kiuchi
Proteins in vivo consist exclusively of L-amino acids. However, the homochirality of amino acids is not always maintained, and D-amino acid residues have been detected in various human tissues.16 The chemical and physical properties of L- and D-amino acids are extremely similar except for their optical character, but the racemization and isomerization of amino acids in proteins have the potential to change protein structure, and post-translational modifications can induce the unfolding of proteins which in turn may contribute to certain diseases.17 Therefore, we hypothesized that in the presence of ocular hypertension, tissues are depleted of L and D amino acids in retina. We demonstrated that the amount and D/L ratio of retinal alanine were reduced in a rat model of ocular hypertension.