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Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Although δ-aminolevulinate is a relatively small molecule (i.e., molecular weight = 131.13) compared to the porfin-based agents described above (e.g., porfimer sodium and temoporfin), it is essentially a prodrug that undergoes metabolic conversion to photoactive porphyrins (e.g., protoporphyrin IX [PpIX]) which accumulate in the treated skin lesions. Interestingly, aminolevulinic acid is an endogenous non-proteinogenic amino acid, and the first intermediate in the porphyrin biosynthesis pathway leading to chlorophyll in plants and heme in mammals. When exposed to oxygen and light of the appropriate wavelength and energy (usually ~37 J/cm² of narrowband red light of 630 nm), the accumulated PpIX transitions to an excited state, which is followed by electron spin transfer to molecular oxygen to generate singlet oxygen atoms (i.e., free radicals). These can further react to form superoxide and hydroxyl radicals, thus exerting a cytotoxic effect. This process is similar to the cytotoxic mechanism of action of porfimer sodium and temoporfin.
Biochemical Parameters and Childhood Nutritional Anemia
Published in Anil Gupta, Biochemical Parameters and the Nutritional Status of Children, 2020
A biochemical test for homocysteine estimates the concentration of homocysteine in plasma. Homocysteine is a non-proteinogenic amino acid. It is a homolog of cysteine amino acid, with the difference being the presence of an additional methylene bridge. It is synthesized from methionine through the elimination of the terminal methyl group.
Molecular Biology Tools to Boost the Production of Natural Products
Published in Luzia Valentina Modolo, Mary Ann Foglio, Brazilian Medicinal Plants, 2019
Luzia Valentina Modolo, Samuel Chaves-Silva, Thamara Ferreira da Silva, Cristiane Jovelina da-Silva
Since the beginning of the 2010s, the CRISPR/Cas9 system has efficiently edited specific genes in bacteria (Jiang et al., 2013), mice (Yin et al., 2014), human cells (Cong et al., 2013) and plants (Ito et al., 2015). In the scope of plants, CRISPR/Cas9 has been used to edit genes in crops such as O. sativa, Solanum lycopersicum, Zea mays and Triticum aestivum (Mishra and Zhao, 2018). This technology was employed to increase the levels of γ-aminobutyric acid (GABA) in S. lycopersicum (Nonaka et al., 2017). GABA is a non-proteinogenic amino acid that possesses hypotensive properties.
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
In addition to the 20 proteinogenic amino acids, more than 800 natural amino acids are known in the literature, while thousands of synthetic amino acids have been reported [98]. The incorporation of non-proteinogenic amino acids that are not found in natural polypeptide chains into a peptide sequence likely will increase the metabolic stability of an analog because the new groups cannot be recognized by the same enzymes. The approach has been applied to many peptide drugs which are on the market [99]. Non-proteinogenic amino acids can be classified into many categories with various terms based on chirality (L vs. D), specific atoms introduced (such as F, S), specific groups introduced (such as CH3), the backbone length (α- vs. β-amino acids), and their combinations. In this section, the most commonly used non-proteinogenic amino acids are discussed as examples.
Type 2 diabetes mellitus and cardiovascular risk; what the pharmacotherapy can change through the epigenetics
Published in Postgraduate Medicine, 2020
Pavlina A. Andreeva–Gateva, Ivelina D. Mihaleva, Ivanka I. Dimova
Homocysteine is a sulfur-containing, toxic non-proteinogenic amino-acid. It is located at a branch-point of multiple metabolic pathways and is produced from methionine by transmethylation. The enzymemethylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate in 5-methyltetrahydrofolate. MTHFR plays a role in the metabolism of folate and the homeostasis of homocysteine. MTHFR is also involved in the transportation of the methyl group to a cytosine base, an epigenetic mechanism. A recent epigenetic study concluded that hypermethylation in the promoter of the MTHFR gene is associated with diabetic retinopathy and nephropathy, as well as some biochemical indicators, as total cholesterol, LDL levels, alpha-1 acid glycoprotein, and total antioxidant capacity [78].
Evolution of compstatin family as therapeutic complement inhibitors
Published in Expert Opinion on Drug Discovery, 2018
New generations of the compstatin family featured with sub-nanomolar affinity and enhanced pharmacokinetic properties were reported [45]. The N-terminal modifications of compstatin CP20 with non-proteinogenic amino acids resulted in two potent analogs Sar-I[CV(1MeW)QDW-Sar-AHRC](NMe)I-NH2, termed as CP30; (D-Tyr)-I[CV(1MeW)QDW-Sar-AHRC](NMe)I-NH2, termed as CP40). CP40 is so far the strongest C3 ligand with subnanomolar binding affinity (KD = 0.5 nM). The computational modeling analysis indicated that the N-terminally modified compstatin analogs formed additional contacts with a shallow pocket in the binding site of C3c. The substitution of non-proteinogenic amino acids is expected to afford an additional benefit of maintaining protection against exopeptidases. Significantly, pharmacokinetic evaluation in non-human primates showed that these analogs have highly beneficial plasma half-life values (CP20, half life = 9.3 h; CP30, half life = 10.1 h; CP40, half life = 11.8 h). In addition, there are strong indications that these compstatin analogs actually follow a target-driven model since C3 is a highly abundant plasma protein.