Newsletter 02/2026 edited by Loredano Pollegioni

D-AAS AND PHYSIOLOGICAL ROLES:

D-amino acid aminotransferase 1 regulates grain chalkiness in rice by modulating endoplasmic reticulum stress response

Dong H, Lei J, Tian Y, Liu J, Yang H, Jiang X, Zhang R, Zhang Y, Chen R, Bao Y, Liu F, Ren Y, Lu Y, Liu X, Liu S, Yang X, Duan E, Teng X, Wang Y, Gu C, Zhang Y, Chen X, Zhang Y, Xu H, Sha R, Xu X, Li R, Li G, Wang Y, Wan J

Proc Natl Acad Sci U S A. 2026 Mar 10;123(10):e2519395123. doi: 10.1073/pnas.2519395123

This study identifies a rice enzyme, OsDAAT1, involved in the metabolism of D-amino acids. The enzyme is expressed in vascular tissues and can interconvert several D-amino acid substrates. Mutation of OsDAAT1 results in accumulation of D-alanine in plant tissues. This metabolic imbalance disrupts protein isomerization and affects enzymes involved in starch and protein synthesis. The resulting stress responses lead to abnormal grain development and increased chalkiness. These findings reveal a previously unrecognized physiological role for Damino
acids in plant metabolism and crop development.

Microglial serine racemase knockout alleviates Alzheimer-like neuropathology and behavioral deficit via lactylation-mediated anti-inflammation

Zhou J, Yang Y, Liu S, Chen J, Liao H, Liang W, Zhang Z, Wang Y, Liu Y, Zhang H, Jiang H, Lin W, Qu J, Barger SW, Wu S

Commun Biol. 2026 Feb 25. doi: 10.1038/s42003-026-09772-y

This study examines the role of serine racemase in microglia and its impact on Alzheimer’s disease. Knockout of the enzyme enhances phagocytosis and reduces inflammation. The effects are mediated through lactylationdependent epigenetic mechanisms. Improved cognitive function and reduced amyloid plaques were observed in mouse models. Sex-specific differences were also identified in D-amino acid metabolism. D-amino acids, especially D-serine, act as critical neuromodulators influencing neuroinflammation and disease progression. This study delineates the functional roles of microglial SR in phagocytosis, inflammatory responses, and learningmemory
behavior in AD-related models, thereby implicating microglial SR as a potential therapeutic target for AD.

Influence of seasonal changes and high salinity conditions on free D-glutamate levels in the reproductive tissues of male kuruma prawn Marsupenaeus japonicus

Onishi A, Shimizu K, Yoshikawa N

J Biochem. 2026 Mar 4:mvag019. doi: 10.1093/jb/mvag019

This study analyzes D- and L-amino acid levels in reproductive tissues of kuruma prawn under varying environmental conditions. D-glutamate is found to accumulate specifically during the breeding season. Its levels are particularly high in seminal receptacles, suggesting active biosynthesis. The D- and L-alanine contents in the testes increased significantly after exposure to high-salinity seawater, whereas L-glutamate content did not change, and D-glutamate increased in some case, suggesting that the increase was due to factors related to reproductive function rather than their response to hyper-osmotic stimulation. Salinity changes have limited influence compared to reproductive processes. The results indicate that D-glutamate is linked to spermatophore regeneration M. japonicus.

Variability in intracellular localization of D-amino acid oxidase in choroid plexus epithelial cells

Ono K, Shishido Y, Yamagishi T, Fukui K

FEBS J. 2026 Feb 17. doi: 10.1111/febs.70459

This study examines the intracellular localization of D-amino acid oxidase in brain epithelial cells. The enzyme is found in multiple compartments including Golgi, endosomes, lysosomes, and peroxisomes. This distribution suggests complex intracellular trafficking. It may enable efficient metabolism of circulating D-serine. In the choroid plexus, DAAO is transported from the Golgi apparatus to endosomes and subsequently distributed to multiple vesicular compartments. The presence of DAAO in peroxisomes, autophagosomes, lysosomes, and exosomes indicated diverse intracellular localization within CPECs. The findings reveal dynamic regulation of enzyme localization. D-amino acids are metabolized across diverse cellular environments, highlighting their physiological significance.

Why are the most lethal pathogens the simplest? Lack of D-amino acid usage, coherent fractal morphology, and Hz-level biological oscillations prevalent in beneficial pathogens

Araujo MM

BioSystems. 2026;262:105713. doi: 10.1016/j.biosystems.2026.105713

This paper proposes a broad theoretical framework linking pathogen lethality with structural simplicity and biochemical traits. The author argues that the most lethal pathogens tend to lack D-amino acid usage, whereas bacterial pathogens that use D-amino acids in peptidoglycan display broader structural complexity. Fractal dimension analysis is used to compare organization across different classes of pathogens. The paper interprets D-amino acid usage as part of a larger pattern associated with more complex and potentially more manageable biological systems. D-amino acids are treated here not as therapeutic agents but as distinguishing biochemical features of bacterial structure and pathogenic organization. Overall, the study offers a speculative systems-level perspective on how D-amino acid usage may correlate with pathogen biology.

Junctional conductance of retinal AII amacrine cell electrical synapses is decreased by NMDA receptors

Cable C, Kuo SP, Newman EA

J Physiol. 2026;604(3):1373-1390. doi: 10.1113/JP286537

This study investigates synaptic plasticity in retinal AII amacrine cells. The authors show that NMDAR activation substantially decreased junctional conductance between AII cells. Relieving the Mg2+ block of NMDARs reduced junctional conductance. Activation of NMDA receptors significantly reduces electrical coupling between cells. The effect is enhanced by coagonists such as D-serine and glycine. Experiments show that both molecules can modulate synaptic conductance. Interestingly, endogenous D-serine is not strictly required for this effect. D-amino acids, particularly D-serine, act as modulators of NMDA receptor signaling and synaptic plasticity. The study adds to mounting evidence that NMDARs mediate plasticity at electrical as well as chemical synapses.

Amino Acid-Based Assessment of Bioavailability and Alteration of Organic Matter in the East Sea

Lee B, Min J-O, Shim C, Ha S-Y, Kim BK, Yoo J, Shin K-H

Ocean Sci J. 2026;61(1):14. doi: 10.1007/s12601-026-00269-7

This study analyzes amino acid composition in marine environments to assess organic matter transformation. Damino acids were found to increase in deeper water layers. Elevated D/L ratios indicate active microbial processing. These changes reflect early diagenesis and organic matter turnover. D-amino acids serve as indicators of microbial activity and degradation processes. They provide valuable insight into ocean biogeochemical cycles.

D-AAs AND PATHOLOGIES:

PROTAC-mediated degradation of peroxisomal D-aspartate oxidase: A novel strategy to modulate D-aspartate homeostasis for schizophrenia treatment

Galli M, Rabattoni V, Cavinato M, Vasile F, Gado I, Ulfat K, Shehi H, Silvani A, Passarella D, Citarella A, Pollegioni L, Nardini M

Eur J Med Chem. 2026 Feb 26;309:118720. doi: 10.1016/j.ejmech.2026.118720

This study explores targeted degradation of human D-aspartate oxidase as a strategy to regulate brain D-aspartate levels. D-Asp is an important neuromodulator influencing NMDA receptor signaling, synaptic plasticity, and cognitive processes. Reduced D-Asp levels and elevated enzyme activity have been associated with schizophrenia. The authors designed heterobifunctional PROTAC molecules combining a DASPO-binding ligand with E3 ligase recruiters. Selected compounds promoted efficient degradation of the enzyme in cellular models. By modulating metabolism of the D-amino acid D-Asp, this strategy offers a potential therapeutic approach for neuropsychiatric disorders.

Quantification of D-Amino Acids in Type 1 Diabetes-Affected Human Serum

Chen S, Lee CJ, Qiu TA, Rubakhin SS, Sweedler JV

J Am Soc Mass Spectrom. 2026 Mar 4;37(3):735-745. doi: 10.1021/jasms.5c00413

This study quantifies multiple D-amino acids in serum samples from type 1 diabetes patients. Advanced LC-MS techniques were used to measure several D/L amino acid pairs. Correlations were identified between D-amino acid levels and clinical markers such as HbA1c and C-peptide. Some D-amino acids increase with disease duration, while others decrease. These trends reflect metabolic and endocrine dysfunction. D-amino acids emerge as potential biomarkers for monitoring disease progression in diabetes.

Microbial and metabolomic profiling of the upper respiratory tract in children with asthma

Xu L, Wan Q, Yang Q, Shen W, Dai Y, Sun H, Huang L, Wang M, Jiang W, Hao C

Front Microbiol. 2026 Feb 17;17:1672589. doi: 10.3389/fmicb.2026.1672589

This study investigates changes in the upper respiratory tract microbiome and metabolome in children with asthma. Differences in microbial composition were associated with disease severity and lung function parameters. Metabolomic analysis revealed several altered biochemical pathways. Among these, amino acid metabolism pathways showed significant changes. D-amino acid metabolism emerged as one of the most affected pathways, suggesting involvement in disease processes. The differential metabolite L-carnitine may be a potential biomarker for asthma assessment. These findings indicate that D-amino acids may contribute to asthma pathophysiology and could serve as biomarkers.

Protective effects of sodium benzoate against toluene-induced reward enhancement, behavioral disturbances, and impaired synaptic plasticity in mice

Hsieh CP, Lee MY, Lin CY, Chan MH, Chen HH

Neurotoxicology. 2026 Mar;113:103403. doi: 10.1016/j.neuro.2026.103403

This study evaluates the neuroprotective effects of sodium benzoate, an inhibitor of D-amino acid oxidase. Inhibition of the enzyme increases levels of D-serine, a co-agonist of NMDA receptors. This leads to improved synaptic plasticity and normalization of neurotransmission. Behavioral impairments induced by toluene exposure were significantly reduced. Cognitive and motor functions were also restored in treated mice. D-amino acids, particularly D-serine, play a central role in regulating neuronal signaling and can be targeted for neuroprotection.

D-AAs AND CHIRALITY:

A reprogrammed genetic code consisting of 32 distinct amino acids

Katoh T, Suga H

Nucleic Acids Res. 2026 Feb 5;54(4):gkag140. doi: 10.1093/nar/gkag140

This study expands the genetic code to allow incorporation of 32 amino acids into peptides. Engineered tRNAs enable reassignment of codons to include noncanonical amino acids. The system supports incorporation of β-,N-methyl, and D-amino acids. This significantly increases chemical diversity in peptide synthesis. The platform enables production of complex macrocyclic peptides. D-amino acids are key components for generating structurally diverse and functionally enhanced biomolecules.

Evaluating intermolecular interactions between amino acid enantiomers

Kitahashi K, Fujihara A

Chem Phys Lett. 2026;883:142543. doi: 10.1016/j.cplett.2025.142543

This study examines intermolecular interactions in chiral amino acid clusters using spectroscopic methods. Differences between homochiral (L-L) and heterochiral (L-D) assemblies were analyzed. Homochiral clusters showed stronger internal hydrogen bonding and lower water adsorption. In contrast, heterochiral clusters containing D-amino acids displayed weaker interactions and higher hydrophilicity. Spectroscopic redshifts confirmed these differences in molecular environments. D-amino acids therefore play a key role in modulating intermolecular interactions and structural organization in chiral systems.

ENZYMES ACTIVE ON D-AAs:

Establishing an assay to evaluate D-amino acid oxidase enzyme kinetics and inhibition using WST-8 redox dye

Miyake K, Enoki Y, Nakazawa Y, Taguchi K, Matsumoto K

FEBS Open Bio. 2026 Feb 24. doi: 10.1002/2211-5463.70217

This study develops a novel assay using WST-8 dye to measure D-amino acid oxidase activity. The method relies on redox reactions to detect enzyme activity through absorbance changes. It was validated using known inhibitors and endogenous metabolites. The assay avoids false positives caused by reducing compounds. It provides a reliable platform for evaluating enzyme kinetics. D-amino acids are essential substrates in this system, enabling precise analysis of DAAO function and inhibition.

D-Amino Acid Transaminases: Structural Diversity, Catalytic Properties, and Potential Applications

Bakunova AK, Shilova SA, Popov VO, Bezsudnova EY

Biochemistry (Moscow). 2026;91(S1):S1-S36. doi: 10.1134/S0006297925603247

This review focuses on D-amino acid transaminases (DATAs), enzymes that catalyze stereoselective synthesis of D-amino acids. These PLP-dependent enzymes exhibit high stereospecificity and broad substrate scope. Their catalytic mechanism involves two-step transamination with pyridoxal phosphate i ntermediates. Structural features such as an open active site enable binding of bulky substrates. D-amino acids are central products of these reactions and play key roles in metabolism and biotechnology. DATAs are highlighted as promising biocatalysts for industrial synthesis of chiral compounds.

Application of D-Amino Acid Oxidase (DAAO) in Bioanalytics

Atroshenko DL, Savin SS, Oretskaya TS, Tishkov VI

Biochemistry (Moscow). 2026; 91 (Suppl 1):S84 – S97. doi: 10.1134/S0006297925604393

This review focuses on D-amino acid oxidase (DAAO) evaluating the main areas of its use in bioanalysis, including clinical diagnostics, monitoring of food and biotechnological processes, and environmental surveillance. The review also addresses factors determining analytical suitability, strategies to broaden selectivity, as well as engineering approaches and structure-guided discovery of new DAAOs. The review also identifies future prospects, such as improving enzyme stability, scaling up portable devices, and integrating biosensing with digital analytics and machine-learning algorithms.

Decoding the substrate specificity landscape of a promiscuous enzyme through multi-substrate mutational scanning

Vanella R, Boult S, Küng C, Nash MA

Nat Commun. 2026 Feb 26. doi: 10.1038/s41467-026-69913-z

This study applies high-throughput mutational scanning to analyze enzyme specificity toward multiple D-amino acids. Thousands of enzyme variants were tested against different D-amino acid substrates. The results reveal that both active-site and distal mutations influence substrate preference. Some variants achieve strong specificity shifts with minimal loss of activity. Combinations of mutations further enhance selectivity. D-amino acids serve as key probes to understand enzyme function and guide rational enzyme engineering.

Structure-guided engineering of substrate specificity in yeast D-aspartate oxidase

Zaitsu S, Imanishi D, Takahashi S

J Biosci Bioeng. 2026 Mar 6:S1389-1723(26)00067-8. doi: 10.1016/j.jbiosc.2026.02.007

This study investigates the structural determinants governing substrate recognition in yeast D-aspartate oxidase. Crystal structure analysis identified Arg243 as a key residue controlling substrate entry and catalytic specificity. Mutagenesis experiments revealed that substitution at this position eliminates activity toward D-Asp while enabling activity toward alternative substrates. Additional mutations were introduced to selectively enhance oxidation of D-His or D-Phe. These engineered enzymes allow selective detection of individual Damino acids in complex mixtures containing multiple stereoisomers. The work highlights the importance of D-amino acids as biochemical substrates and demonstrates how enzyme specificity toward different D-amino acids can be rationally engineered.

D-AAs AND BIOTECHNOLOGY:

One-Pot Synthesis of D-Amino Acids Using a Soluble and Immobilized LAAO–CAT–D-Transaminase Cascade

Berelsmann N, Tiedemann S, von Langermann J, von Mollard G.F, Heinks T

ChemCatChem. 2026;18(5):e01831. doi: 10.1002/cctc.202501831

This study develops a one-pot enzymatic cascade for converting L-amino acids into enantiomerically pure D-amino acids. The system combines L-amino acid oxidase, catalase, and an R-selective transaminase to generate several D-amino acids, including phenylalanine, methionine, histidine, and tryptophan. Optimization of enzyme loading produced high conversions and excellent enantiomeric excess. The authors also co-immobilized the enzymes on functionalized beads, which improved catalytic efficiency and affected the usable pH range. D-amino acids are the direct target products here, and the study provides a practical biocatalytic route for their sustainable preparative synthesis. This work is relevant for pharmaceutical and fine-chemical production of Damino- acid building blocks.

Stereoselective design of amino acid bioconjugates: targeting strategies and physicochemical optimization

Mandal S, Choudhary R, Konkimalla VB

RSC Med Chem. 2026;17(1):163-207. doi: 10.1039/d5md00760g

This review discusses the design of amino acid-based bioconjugates for improving drug delivery and efficacy. Amino acids enable targeted transport through specific cellular transporters and enhance pharmacokinetics. The authors highlight how stereochemistry influences stability, bioavailability, and therapeutic performance. In particular, D-amino acids significantly improve resistance to proteolytic degradation and enhance bioactivity. In contrast, L-amino acids contribute to receptor recognition and metabolic compatibility. The work emphasizes the importance of combining both forms to optimize next-generation drug conjugates.

Engaging Unstabilized Alkyl Radicals with Pyridoxal Radical Biocatalysis: Enantiodivergent Synthesis of Aliphatic Non-Canonical Amino Acids

Cheng L, Chen J, Bo Z., Zhang X, Liu P, Yang Y

J. American Chemical Society. 2026, 148 (5), 5092 – 5101. doi: 10.1021/jacs.5c16304

Repurposing and directed evolution of pyridoxal phosphate (PLP)-dependent tryptophan synthases were used to generate an open-shell enzyme platform capable of intercepting transient alkyl radicals for the efficient and enantioselective synthesis of aliphatic noncanonical amino acids. A potentially general strategy for generating and utilizing unstabilized alkyl radicals was generated, underscoring the synthetic potential of radical pyridoxal biocatalysts for stereodivergent amino acid construction.

Novel Technologies in Periprosthetic Joint Infections: Emerging Therapeutics

Magruder ML, Heckmann ND, Lieberman JR, Scuderi G, Lustig S, Parvizi J, Mont MA

J Arthroplasty. 2026;41(2):560-568. doi: 10.1016/j.arth.2025.06.086

This review summarizes emerging technologies for treating periprosthetic joint infections. Biofilm formation remains a major challenge in infection control. Several innovative approaches are discussed, including bacteriophages and photothermal therapy. One strategy combines near-infrared activation with D-amino acids to disrupt biofilms. This enhances bacterial clearance and improves treatment outcomes. D-amino acids therefore serve as adjuvants that weaken biofilm structure and improve antimicrobial efficacy. Future research should focus on validating their efficacy and safety through large-scale clinical trials and integrating them into existing treatment protocols.

Synthesis and biological potency of novel optically active α-(arylthio) alkanoic acid derived from amino acids

Kakabor MK, Hadi Chawishli L

Journal of Sulfur Chemistry. 2026;47 (1):67–86. doi: 10.1080/17415993.2025.2579614

This paper focuses on the synthesis and biological evaluation of optically active α-(arylthio)alkanoic acids derived from L- and D-amino acids such as phenylalanine, valine, and leucine. A two-step synthetic pathway was used for the preparation of the compounds, which included bromination of amino acids followed by subsequent nucleophilic substitution with thiophenol or 4-bromothiophenol. Compound (18) exhibited the strongest antimicrobial activity, significantly inhibiting the growth of Staphylococcus aureus and Candida albicans, and the strongest antioxidant activity. On the other hand, compound (15) presented the best anticancer activity, inhibiting the cell viability of breast cancer (MCF7) cell lines by 60%.

Concise construction of β-branched aromatic D-amino acids via transaminasecatalyzed
dynamic kinetic resolution

Liu Z, Zhai W, Zeng Z, Meng X, Shi Y, Huang J, Su P, Yan X, Yang LC

Nat Commun. 2026 Mar 6. doi: 10.1038/s41467-026-70265-x

This study presents a biocatalytic strategy for synthesizing β-branched aromatic D-amino acids. The authors used a PLP-dependent transaminase combined with dynamic kinetic resolution to achieve high stereoselectivity. The system produced a wide range of D-amino acid analogues with excellent yields and enantiomeric purity. These molecules represent important noncanonical amino acids with pharmaceutical relevance. The synthesized compounds were successfully incorporated into modifications of the peptide drug lanreotide. The work demonstrates the growing importance of D-amino acids as synthetic building blocks for designing therapeutically optimized peptide and drug molecules.

Functionalized nanodiamonds-toward innovative antitumor approaches

Boreggio M, Rosini E, Moncalvo F, Zavodna T, Hradilova S, Cellesi F, Pollegioni L, Polakova K, Fasoli E

Nano Express. 2026;7(1):015008. doi: 10.1088/2632-959X/ae378a

This study explores the use of D-amino acid oxidase in enzyme-activated cancer therapy. The enzyme catalyzes oxidation of D-amino acids to produce hydrogen peroxide. This generates cytotoxic effects selectively in tumor environments. The contribution of the protein corona to both cytotoxicity and oxidative stress was also evaluated: PEG-NDs-DAAO seemed to exhibit promising antitumor characteristics (a biocompatible PC may contribute to potentially prolong blood circulation time and the increased cytotoxicity against human breast cancer cells). The approach can be integrated with nanomaterials for targeted delivery. It represents a promising strategy for anticancer treatment. D-amino acids serve as substrates for generating therapeutic reactive species in cancer therapy.

Combined effects of quercetagetin and D-amino acids against Pseudomonas aeruginosa: Anti-quorum sensing, antibacterial, and antibiofilm activities

Ji M, Li J, Fan L, Wang L, Huang S

Food Bioscience. 2026;77:108393. doi: 10.1016/j.fbio.2026.108393

This study investigates the combined antibacterial effects of quercetagetin (Que), a quorum sensing inhibitor, and D-amino acids against Pseudomonas aeruginosa. Que alone suppresses quorum sensing-regulated virulence but shows limited antibiofilm activity at sub-inhibitory concentrations. When combined with D-amino acids such as D-leucine or D-tryptophan, a strong synergistic effect is observed on both planktonic and biofilm cells. The treatment significantly reduces bacterial survival, biofilm biomass, and structural integrity. Mechanistically, the combination disrupts the biofilm matrix, increases membrane permeability, and inhibits key metabolic enzymes. D-amino acids play a crucial role as adjuvants, enhancing antibiofilm activity and improving the efficacy of quorum sensing inhibition strategies.

Unified total synthesis of colisporifungin, ophiotine and verruculin

Akiyama K, Fujiwara K

Tetrahedron. 2026;192:135123. doi: 10.1016/j.tet.2025.135123

This study describes a unified total synthesis of three cyclic lipohexadepsipeptides sharing a common framework. The synthetic route is convergent and relies on solution-phase peptide synthesis followed by final-stage connection and cyclization. A key design element is the efficient assembly of a scaffold containing three D-amino acids and β-alanine. Early installation of the fatty acid moiety also helped streamline the synthesis. D-amino acids are essential structural elements of these natural products and are central to recreating their native peptide framework. The work demonstrates an efficient strategy for preparing complex peptide natural products containing multiple D-amino acid residues.

Protective role of oligochitosan in intestinal homeostasis to Edwardsiella ictaluri in hybrid grouper

Ma L, Chen Z, He Z, Zheng X, Li Y, Zhou C, Lin L, Shi F

Aquaculture. 2026;610:742923. doi: 10.1016/j.aquaculture.2025.742923

This study investigates the effects of oligochitosan on intestinal health in infected fish. Infection disrupts gut structure, microbiota, and metabolic pathways. Oligochitosan treatment restores intestinal integrity and microbial balance. Metabolomic analysis shows recovery of amino acid metabolism pathways. D-amino acid metabolism is significantly affected and restored by treatment, indicating its role in host health. Oligochitosan can alleviate E. ictaluri induced by enhancing intestinal tissue integrity and antioxidant defense, maintaining intestinal flora balance, and regulating amino acid metabolism. These findings highlight the importance of D-amino acids in gut physiology.

A Robust Nonfouling Biosensor Based on an Engineered Multifunctional Monocyclic Peptide for Electrochemical Detection of Biomarkers in Human Blood

Zhu B, Han R, Wang W, Cheng S, Luo X

Anal Chem. 2026 Feb 17;98(6):5095-5104. doi: 10.1021/acs.analchem.5c07842

This study reports a biosensor based on a monocyclic peptide designed for HER2 detection. The peptide incorporates a D-amino acid sequence for target recognition. The design improves resistance to enzymatic degradation and biofouling. This results in high sensitivity and stability in complex biological samples. The sensor shows excellent agreement with clinical diagnostic methods. D-amino acids enhance durability and performance of biosensors in real biological environments. The assay results for HER2 in clinical blood samples were consistent with those obtained from ELISA.

A generalizable assay for intracellular accumulation to profile cytosolic drug delivery in mammalian cells

Bhandari S, Ongwae GM, Dash R, Liu Z, Chordia MD, He Y, Pires MM

Commun Chem. 2026 Feb 6;9(1):94. doi: 10.1038/s42004-026-01898-8

This study introduces the CHAMP assay to measure cytosolic delivery of biomolecules. The method distinguishes between membrane-bound and truly internalized compounds. It was applied to peptides, proteins, and small molecules. Structural features influencing uptake were systematically analyzed. D-amino acid substitutions were found to significantly affect cellular penetration and accumulation. This method provides a robust platform for screening cytosolic accumulation while minimizing the confounding effects of large tags on molecular permeability, potentially accelerating the development of therapeutics targeting intracellular pathways.

D-AAs IN BACTERIA:

Cell wall hydrolysis promotes a second wave of transpeptidation to achieve cell separation following septation in Bacillus subtilis

Patel V, Hsu YP, Debnath M, Kearns DB, VanNieuwenhze MS, Brun YV

Nat Commun. 2026 Feb 12. doi: 10.1038/s41467-026-69404-1

This study uncovers a new step in bacterial cell division involving post-septational transpeptidation. Fluorescent D-amino acids were used to track peptidoglycan remodeling in real time. The results show that existing cell wall material is reshaped rather than newly synthesized. Coordination between hydrolysis and transpeptidation is essential for proper cell separation. Disruption of this process impairs cytokinesis. D-amino acids serve as powerful probes to visualize and understand bacterial cell wall dynamics. This study reveals a mechanism whereby the coordinated activities of PG hydrolysis and transpeptidation ensure successful cytokinesis

Lactobacillus fermentum supplementation modulates jejunal microbiota, metabolome, and morphology in yaks under high-energy feeding

Yu Q, Huang C, Bao P, Li N, Zhang M, Wang T, Ma C, Deng J, Cao X, Jia J, Yan P

Anim Microbiome. 2026 Feb 12;8(1):17. doi: 10.1186/s42523-025-00479-9

This study investigates the effects of Lactobacillus fermentum supplementation on gut health in yaks. The treatment improves intestinal morphology and enhances beneficial microbial populations. Metabolomic analysis reveals significant changes in multiple metabolic pathways. Among these, amino acid metabolism is strongly affected. D-amino acid metabolism is significantly modulated and linked to improved metabolic outcomes.

D-AAs IN PEPTIDES AND PROTEINS:

Discovery of Encrypted Peptides in a Human Matrix Metallopeptidase

Gaglione R, Schibeci M, Piccolo E, Culurciello R, Zannella C, Mensitieri F, Dal Piaz F, Cafaro V, De Filippis A, Pizzo E, Notomista E, Torres MDT, de la Fuente-Nunez C, Arciello A

JACS Au. 2025 Dec 10;6(1):124-143. doi: 10.1021/jacsau.5c00947

This study identifies antimicrobial peptides derived from human proteins. These peptides show broad-spectrum activity against bacteria and viruses. A fully D-amino acid version of the lead peptide was synthesized. The modified peptide retained activity and showed improved stability. It also demonstrated efficacy in animal infection models. These findings underscore the therapeutic promise of human protein-derived encrypted peptides and highlight proteome mining as a viable strategy for identifying host-compatible anti-infectives. Damino acids enhance resistance to degradation while preserving biological function.

Computational analysis of structural features in tetrameric amyloid β1-42 peptides containing D-Asp residues

Mizuno A, Nakayoshi T, Inaoka K, Shingaki A, Kato K, Oda A

Chemistry Letters. 2026;55(2):upag015. doi: 10.1093/chemle/upag015

This study uses molecular dynamics simulations to investigate amyloid β1–42 peptides containing D-aspartate residues. The authors modeled a fully stereoinverted variant in which all Asp residues were converted to D-Asp. The results show that D-Asp substitutions significantly affect peptide structure and aggregation behavior. In particular, D-Asp at positions 7 and 23 strongly disrupts β-sheet formation. The effect of D-Asp1 is comparatively weaker. These findings highlight how D-amino acids can alter protein folding and may influence the progression of amyloid-related diseases.

Impact of the Arrangement Modes of the Antimicrobial Motifs WWR-7 and its Analogs in CAMPs on Their Therapeutic Properties

Yadav M, Singh HV, Basu S, Thummer RP, Chatterjee S

Chemistry – An Asian Journal. 2026;21 (1): art. no. e70330. doi: 10.1002/asia.70330

The impact of the antimicrobial motif (WWR-7, LRWWRRLNH2) arrangement were studied, either in tandem or as branches, on the structure-activity of cationic dimeric antimicrobial peptides (CAMPs). WWR-7 was modified in charge (Arg to Leu) and amino acid composition (Leu to Val/ L- to D- amino acids) to generate dimers aimed at improving their activity, selectivity, and stability. WWR-14dV, 2BWWR-7 V, and 2BWWR-7dV showed high, salttolerant, and fast bactericidal efficacy against ESKAPE pathogens, drug-resistant pathogens (MRSA/VRSA), and fungus Candida albicans. Additionally, these peptides exhibited high antibiofilm efficacy against MRSA and Pseudomonas aeruginosa, protease/serum stability, nondevelopment of resistance against pathogens, high selectivity, and ability to be used in combination with ciprofloxacin to mitigate MRSA infections.

Biotinylated heptapeptides containing D-amino acids suppress cysteinyl leukotriene production and allergic airway inflammation

Ohira M, Harada H, Yuki H, Tsumuraya M,· Nozaki E, Nukimizu R, Uta D, Ebina K, Matsumoto T, Sato A.

J Incl Phenom Macrocycl Chem. 2026; doi: 10.1007/s10989-026-10817-3

This study examines biotinylated heptapeptides containing D-amino acids as inhibitors of mast cell activation  and allergic inflammation. Among the tested compounds, Peptide 2 strongly reduced cysteinyl leukotriene release from IgE/antigen-activated mast cells and also inhibited LTC4-induced edema in mice. Intranasal administration significantly decreased inflammatory cell infiltration, especially eosinophils and lymphocytes, in an allergic airway inflammation model. The peptide was more effective locally than after systemic administration. D-amino acids are integral to the bioactive peptide design and appear to contribute to its antiallergic efficacy and stability. The work suggests that D-amino-acid-containing peptides may represent a new therapeutic strategy for allergic disease..

Expression of a strain-specific non-ribosomal peptide synthetase from Aspergillus lentulus

Kishimoto S, Masuyama Y, Watanabe K

J Antibiotics. 2026;79(3):205-213. doi: 10.1038/s41429-025-00887-8

This study identifies a new fungal alkaloid produced by a strain-specific biosynthetic gene cluster. The compound, lentoquinazoline, was characterized using NMR and stereochemical analysis. Unlike typical nonribosomal peptide synthetase NRPS products, 6-6-6 tricyclic quinazoline-synthesizing NRPSs typically contain an epimerase domain and incorporate one molecule of D-amino acid to the product, LeqA was found to introduce only L-amino acids due to the mutations in the active site of the epimerase domain.

Widespread hypermodified β-helical peptides in common bacteria

Vadakumchery L, Meier CM, Forneris CC, Paoli L, Courvoisier-Clément A, Bhushan A, Lotti A, Padhi C, Sunagawa S, Gossert AD, Piel J

Chem. 2026;12(3):102877. doi: 10.1016/j.chempr.2025.102877

This study reports the discovery of a widespread family of hypermodified ribosomal peptides, termed origamins, in diverse and well-known bacteria. These peptides share striking similarities with polytheonamides, including extensive post-translational modifications and β-helical structures. Notably, they contain a large number of noncanonical residues, including multiple D-amino acids, which are critical for their structural organization. These peptides function as transmembrane ion channels with cytotoxic activity. Their presence in human associated bacteria suggests a potential role in host–microbiome interactions. D-amino acids are key structural elements that contribute to stability, folding, and biological function of these complex peptides.

D-amino acid substitution and cyclization enhance the stability and antimicrobial activity of arginine-rich peptides

Mendes B, Castelletto V, Hamley IW, Barrett G

Microbiology (Reading). 2026 Feb;172(2):001657. doi: 10.1099/mic.0.001657

This study investigates strategies to improve stability of arginine-rich antimicrobial peptides. D-amino acid substitution and cyclization were introduced into peptide sequences. These modifications significantly increased resistance to proteolytic degradation. The modified peptides retained strong antibacterial and antibiofilm activity. Mechanistic studies revealed complex effects on membrane disruption and gene expression. D-amino acids are key to enhancing stability and therapeutic potential of antimicrobial peptides

Functional Peptide-Based Biomaterials for Pharmaceutical Application: Sequences, Mechanisms, and Optimization Strategies

Yu D, Han N, Son H, Kim SJ, Kweon S

J Funct Biomater. 2026 Jan 13;17(1):37. doi: 10.3390/jfb17010037

This review summarizes advances in peptide-based biomaterials for drug delivery. It covers different classes of peptides and their functional mechanisms. Various optimization strategies are discussed, including cyclization and sequence modification. These approaches improve stability, targeting, and bioavailability. Incorporation of D-amino acids is highlighted as a key strategy to enhance resistance to degradation and functional performance. This supports their widespread use in pharmaceutical design.

A novel peptide blocking CD93/IGFBP7 interaction normalizes tumor vessels and
synergizes with radiotherapy for cancer immunotherapy

Qian Y, Zhang Q, Wu Y, Sun Y, Cheng Y, Shi P, Wang Q, Qiu L, Wang M, Zhao W, Zhai W, Li L

Pharmacol Res. 2026 Mar;225:108118. doi: 10.1016/j.phrs.2026.108118

This study identifies a peptide that blocks CD93/IGFBP7 interaction to normalize tumor vasculature. D-amino acid modification and retro-inversion improve peptide activity and stability. The optimized peptide enhances immune cell infiltration into tumors. It also synergizes with radiotherapy to suppress tumor growth. Improved vascular function contributes to better therapeutic outcomes. Overall, a novel peptide blocking CD93/IGFBP7 interaction was identified, aimed at normalize tumor vascular function, promote a favorable tumor microenvironment for the therapeutic intervention.

On-site self-assembly of glycopeptide triggered by bioorthogonal ligation to metabolically labeled bacteria for promoting tissue regeneration in methicillinresistant
Staphylococcus aureus (MRSA)-Infected wounds

Zhang J, An D, Wang X, Wen R, Yu Y, Zhang Z, Wang M, Qing W, Yi Q, Wu Y

Biomaterials. 2026 Jul;330:124030. doi: 10.1016/j.biomaterials.2026.124030

This study develops a strategy for selectively targeting bacteria using metabolically incorporated D-amino acid derivatives. These molecules introduce reactive groups into bacterial cell walls. A designed peptide binds specifically to labeled bacteria and self-assembles into antimicrobial nanostructures. The system disrupts bacterial membranes and inhibits growth. It also promotes immune activation and tissue regeneration. D-amino acids act as targeting tools enabling precise and localized antimicrobial therapy. In a rat model of MRSA infected wounds, the treatment strategy demonstrated comprehensive efficacy by facilitating rapid MRSA clearance, reducing destructive inflammation, stimulating robust angiogenesis, and enhancing collagen deposition, thereby markedly accelerating tissue regeneration.

On-Resin DIAMSAR-Conjugated CD38-Targeted Peptides and Their Inverso and Dimeric-Inverso Analogs for PET Imaging of Multiple Myeloma

Sharma AK, Tang R, Zheleznyak A, Manion B, Teubner E, Prior JL, Bauer T, Dyer MR, Lees S, Kelly K, Shokeen M

Bioconjug Chem. 2026 Feb 11. doi: 10.1021/acs.bioconjchem.5c00577

This study develops peptide-based PET imaging agents targeting CD38 in multiple myeloma. Substitution of L-amino acids with D-amino acids improves peptide stability in serum. D-amino acid-containing peptides also show enhanced binding affinity to the target receptor. Dimerization further increases avidity and imaging signal. In vivo studies confirm improved tumor localization. D-amino acids significantly enhance stability, binding, and overall imaging performance of peptide tracers.

Supramolecular net-suppressor drives tumor vascular-immune microenvironment remodeling with spatiotemporal synchronization for renal
cancer therapy

Wang J, Jin X, Wu X, Wang Y, Sun X, Li J, Teng Y, Yan Y, Li C, Lv Y, Jian L, Yuan K, Wang L

Mater Horiz. 2026 Feb 18. doi: 10.1039/d5mh01936b

This study introduces a multifunctional peptide (RING1) that targets tumor vasculature and immune checkpoints. The peptide self-assembles into nanonetworks within the tumor microenvironment. This enhances vascular normalization and immune cell infiltration. The design integrates multiple therapeutic mechanisms into a single molecule. Incorporation of D-amino acids improves peptide stability and tumor accumulation. RING1 represents a novel therapeutic strategy that remodels the tumor vascular-immune microenvironment with spatiotemporal synchronization via self-assembly, offering a promising alternative to conventional combination therapies.

Overcoming Proteolytic Instability in a β-Turn Antimicrobial Peptide via Cyclization and Stereochemical Inversion to Combat MDR Bacteria

Wang T, Tian L, Zeng J, Ning Z, Zhang L, Zhao C, Jiang S, Zeng C, Han J, Luan L, Ye W, Meng Q

J Med Chem. 2026 Feb 26;69(4):4726-4744. doi: 10.1021/acs.jmedchem.5c03372

This study designs cyclized β-turn antimicrobial peptides with improved stability. Incorporation of D-amino acids enhances resistance to enzymatic degradation. The modified peptide shows strong activity against multidrugresistant bacteria. It also demonstrates low toxicity and synergistic effects with antibiotics. In vivo experiments confirm its therapeutic potential. D-amino acids are essential for improving peptide stability while maintaining antimicrobial efficacy.

A one-step, resin-compatible Cys-Trp cross-linking system opens a new avenue for stapled peptide therapeutics

Denda M, Kohmura Y, Kobayashi D, Yoshimaru T, Fukuda S, Ando H, Ishida T, Katagiri T, Otaka A

Bioorg Med Chem. 2026 Mar 7;137:118622. doi: 10.1016/j.bmc.2026.118622

This study introduces a one-pot Cys–Trp cross-linking strategy to generate stapled peptides targeting protein–protein interactions. The method allows peptide stapling to occur simultaneously with global deprotection and resin cleavage, simplifying synthesis. The approach was applied to an estrogen receptor α regulatory peptide designed to disrupt pathogenic interactions in breast cancer. The resulting stapled peptide displayed strong and sustained antiproliferative activity comparable to previously reported analogues. Importantly, stereochemical substitutions at the stapling positions were explored. Incorporation of D-amino acids decreased α-helicity, demonstrating how D-amino acids can modulate peptide conformation and structural stability.

Dual Amino Acid Swap in MUC7-Derived Peptide Enhances Resistance and
Modulates Zn(II) and Cu(II) Complex Stability, Secondary Structure and
Antimicrobial Activity

Szarszoń K, Kachnowicz J, Janek T, Domínguez-Martin A, Jezierska A, Wątły J

Inorg Chem. 2026 Mar 16;65(10):5611-5626. doi: 10.1021/acs.inorgchem.5c05849

This study investigates the effect of introducing two D-amino acids into a MUC7-derived peptide. The modification increases resistance to proteolytic degradation and enhances peptide stability. Detailed spectroscopic and computational analyses reveal changes in metal coordination with Cu(II) and Zn(II). The modified peptide forms more stable complexes and exhibits improved antimicrobial and antibiofilm activity. It selectively targets oral pathogens while remaining non-toxic to human cells. D-amino acids play a key role in enhancing structural flexibility, stability, and biological activity of antimicrobial peptides.

D-AAs AND ANALYTICAL METHODS (AND FOODS):

Machine-learning assisted design of ultra-sensitive chiral molecularlyimprinted sensor for detection of D-Serine: A potential Alzheimer biomarker

Mansour SS, Mahmoud AM, Moustafa AA, Nashat NW

Electrochimica Acta. 2026;554:148344. doi: 10.1016/j.electacta.2026.148344

This study reports a chiral molecularly imprinted electrochemical sensor for highly sensitive detection of Dserine. The authors used methyldopa as a functional monomer and optimized sensor performance through response surface methodology and artificial neural networks. The resulting device showed excellent selectivity for D-serine over the L-enantiomer and a very wide linear detection range (1.0 × 10⁻¹³ M to 1.0 × 10⁻¹⁰ M for D‑serine). The sensor also proved suitable for direct application in human plasma. D-amino acids, specifically Dserine, are central here as clinically relevant biomarkers, and the work focuses on their selective chiral recognition. This approach could support point-of-care monitoring of D-serine in Alzheimer’s disease research and diagnostics.

Two-Dimensional LC–MS/MS Determination of Chiral Amino Acids in Real-World Samples

Ishii C, Hamase K

Methods Mol Biol. 2026;2994:231-244. doi: 10.1007/978-1-0716-5023-3_12

This chapter describes analytical methods for detecting chiral amino acids in biological samples. Two dimensional LC–MS/MS enables highly sensitive and selective quantification. The approach is suitable for complex matrices such as plasma and urine. D-amino acids are present at trace levels but have important physiological roles. Accurate detection is essential for biomarker discovery. The method supports clinical and biochemical research involving D-amino acids.

Carbon dot-based fluorescent sensor array for multi-target chiral discrimination of all amino acids

Shi T, Liuye S, Chen Y, Yang L, Cao X

Microchemical Journal. 2026; 221,:art. no. 116965. doi: 10.1016/j.microc.2026.116965

Here, a fluorescent sensor array based on chiral carbon dots (CCDs) and metal ions was built, realizing rapid, multi-target detection of all D- and L-amino acids, as well as their mixtures in artificial saliva. The developed 6-channel array successfully identified all natural amino acids and their enantiomers within 30 s. Furthermore, it enabled quantitative analysis and discrimination of mixtures containing different ratios of D-amino acids in saliva, achieving a detection limit for D-Ala of 1.08 μmol/L, well suited for gastric cancer analysis.

INFORMATION

The D-amino acids International Research Center “DAAIR“ has been established in 2019 with the aim to support and perform scientific research projects and activities on the field of D-amino acids. The Center is aimed to represent a pole of excellence at international level for dissemination and research involving the D-amino acids (Director Silvia Sacchi).

Info@d-aminoacids.com

director@d-aminoacids.com

D-AMINO ACIDS INTERNATIONAL RESEARCH CENTER

INFO@D-AMINOACIDS.COM