Promising Application of D-Amino Acids toward Clinical Therapy

Abstract

The versatile roles of D-amino acids (D-AAs) in foods, diseases, and organisms, etc., have been widely reported. They have been regarded, not only as biomarkers of diseases but also as regulators of the physiological function of organisms. Over the past few decades, increasing data has revealed that D-AAs have great potential in treating disease. D-AAs also showed overwhelming success in disengaging biofilm, which might provide promise to inhibit microbial infection. Moreover, it can effectively restrain the growth of cancer cells. Herein, we reviewed recent reports on the potential of D-AAs as therapeutic agents for treating neurological disease or tissue/organ injury, ameliorating reproduction function, preventing biofilm infection, and inhibiting cancer cell growth. Additionally, we also reviewed the potential application of D-AAs in drug modification, such as improving biostability and efficiency, which has a better effect on therapy or diagnosis.

Keywords: D-amino acid; protective effect; therapeutic effect.

Figure 1

D-AAs are transformed or assembled by varied enzymes, both of them are reversible; (A) racemization via a planar carbanion intermediate; (B) the amino of one of D-AA is transferred to an α-ketoacid by D-AA aminotransferase, and generating the corresponding D-AA.

Figure 2

The relevant diseases/symptoms improved by D-AAs administration were through its direct and indirect action. NMDAR pathway is vital to ameliorate many symptoms with respect to psychological and physiological defects, such as depression, and vision, etc. H₂S can be generated from the metabolic process of D-AA. H₂S is important to gastrointestinal function, and inflammation process, etc. D-AAs have both direct and indirect action on anti-oxidative damage, whereas some acoustic protection, and radiation protection, etc. are associated with anti-oxidative damage. Inhibiting tumor cell growth, disengaging biofilm, regulating intestinal bacterial, and regulating T cells, etc. are important elements of the protective effect of D-AAs.

Figure 3

H₂S is generated from D-Cys via two processes, oxidation of DAAO and catalysis of 3MST. During oxidation, some D-AAs are eventually converted into H₂O₂, NH₃, and α-ketoacid. Apart from H₂S, pyruvate is another metallic form of 3MP. Some functions of D-Cys are associated with the generation of H₂S.

Figure 4

D-Met can be an otoprotective agent through its direct and indirect anti-oxidative action. It can be a free radical scavenger due to its reversible oxidation. Protecting critical enzymes, bonding to cisplatin, preventing the efflux of glutathione, and increasing cellular levels, etc., which are critical elements for indirect anti-oxidative function.

Figure 5

D-Val and D-Trp are incorporated into some antibiotics and analgesics drug, respectively.

Figure 6

The possible antibiotic mechanism of penicillin. The peptidoglycan contains temporary D-alanyl-D-ala groups during crosslinking processes. Crosslink would be terminated while D-alanyl-D-ala was replaced by penicillin. The glycan strands consist of alternating N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc). The crosslinking of glycan strands is through the connection of meso-diaminopimelic acid (meso-Dap) and D-Ala.