Newsletter 04/2026 edited by Loredano Pollegioni

D-AAS AND PHYSIOLOGICAL ROLES:

D-Amino Acids in Marine and Terrestrial Environments: Diversity and Uniformity of Their Microbial Catabolism

Yu Y, Zhang JL, Chen XL, Zhang YQ, Zhong WH

Environ Microbiol. 2026 Jul;28(7):e70371. doi: 10.1111/1462-2920.70371

This review summarizes current knowledge on the sources, distribution, and environmental fate of D-amino acids (D-AAs), emphasizing their ecological importance in marine and terrestrial ecosystems. Although D-AAs are not incorporated into ribosomal proteins, they play essential roles in microbial physiology and are actively recycled through conserved bacterial catabolic pathways that convert them into α-keto acids, L-amino acids, or glycine. The authors highlight key knowledge gaps, including the limited understanding of fungal contributions and DAA-catabolizing microbial communities in terrestrial environments. Overall, the review underscores the central role of microbial D-AA metabolism in global biogeochemical cycles and identifies important directions for future ecological and microbiological research.

Dietary riboflavin blocks the cGAS-STING pathway to curb hypoxia-induced hepatic inflammation in sub-adult grass carp (Ctenopharyngodon idella)

Zhong L, Feng L, Wu P, Jiang W, Zhang H, Ma Y, Liu Y, Mi H, Wu F, Zhang L, Zhou X

Anim Nutr. 2026 Jun 2;26:478-492. doi: 10.1016/j.aninu.2026.01.012

This study investigated the effects of dietary riboflavin (vitamin B2) supplementation on growth and hypoxiainduced liver inflammation in grass carp. Appropriate VB2 levels improved growth performance, enhanced mitochondrial function, and reduced hepatic damage and inflammatory responses under hypoxic conditions. Riboflavin supplementation also increased D-amino acid oxidase (DAAO) activity, indicating improved flavoprotein function and supporting its use as a biomarker for vitamin B2 nutritional status. These findings highlight the physiological relevance of DAAO in fish metabolism and demonstrate the importance of adequate riboflavin supplementation for maintaining metabolic and hepatic health under environmental stress.

Metabolomic cues from Salmonella typhi drive neuroimmune modulations and behavioural adaptation in Caenorhabditis elegans

Balamurugan K

Dev Comp Immunol. 2026 Jul;180:105647. doi: 10.1016/j.dci.2026.105647

This study demonstrates that metabolites produced by Salmonella Typhi can induce infection-like responses in Caenorhabditis elegans even in the absence of live bacteria. Metabolomic analysis revealed enrichment of several pathways, including D-amino acid metabolism, together with neuroactive and redox-active compounds that modulate dopaminergic signaling, immune activation, and insulin signaling. These metabolite-driven changes triggered heritable avoidance behavior and host defense responses through the gut–brain axis. The involvement of D-amino acid metabolism highlights its potential contribution to host–microbe communication and neuroimmune regulation during bacterial infection.

D-AAs AND PATHOLOGIES:

Evaluation of the Association between Age, Sex and D-Amino Acid-Based Estimation of Glomerular Filtration Rate

Fukae S, Sakai S, Tanaka R, Taniguchi A, Kawamura M, Kimura-Ohba S, Nakazawa S, Horio M, Takahara S, Imamura R, Yamada M, Oda T, Konno O, Iwamoto H, Isaka Y, Mizui M, Nonomura N, Kakuta Y, Kimura T

Clin J Am Soc Nephrol. 2026 Jun 9. doi: 10.2215/CJN.0000001108

This study evaluated the use of the D-serine and D-asparagine as biomarkers for estimating glomerular filtration rate (GFR). A prediction model based on circulating D-amino acid levels achieved accuracy comparable to conventional creatinine-based equations while showing minimal dependence on age and only a minor influence of sex. Because D-amino acids undergo near-ideal renal clearance and are less affected by body size, they provide a more robust approach to GFR estimation across different patient populations. These findings highlight the clinical potential of D-amino acids as reliable biomarkers for kidney function assessment with broad applicability across age groups.

D-Amino acid oxidase inhibitor ameliorates cerebral ischemia-reperfusion injury in rats via D-Serine/GluN2A/BDNF signaling pathway

Huang J, Zhu J, Zheng H, Zhu E, Yang C, Ying L, Zhou Y, Liu H

Eur J Pharmacol. 2026 Jun 3;1030:179051. doi: 10.1016/j.ejphar.2026.179051

This study investigated the neuroprotective effects of D-amino acid oxidase (DAAO) inhibition in cerebral ischemia–reperfusion injury, demonstrating that its benefits are largely mediated by increased cerebral D-serine levels. Pharmacological inhibition of DAAO and D-serine supplementation significantly reduced infarct size, improved neurological and cognitive outcomes, and enhanced neuronal survival in both in vivo and in vitro models. Mechanistically, D-serine promoted activation of the GluN2A/BDNF signaling pathway, increased synaptic plasticity markers, and suppressed apoptosis-related p38 MAPK phosphorylation. These findings highlight the therapeutic potential of targeting D-amino acid metabolism, particularly D-serine and DAAO, for the treatment of ischemic stroke and associated cognitive impairment.

Identification of Potential Plasma Biomarkers of Abdominal Aortic Aneurysm Using a Metabolomics Approach

Wang W, Chen Z, Tang X, Wang X, Wu L, Xiang W, Zhang Z, Feng H, Wu J, Zheng Y

Curr Mol Med. 2026 May 20. doi: 10.2174/0115665240435737260306084312

This metabolomics study identified distinct plasma metabolic signatures associated with abdominal aortic aneurysm (AAA), revealing alterations in pathways including retinol, glutathione, purine, and D-amino acid metabolism. Among 115 differentially abundant metabolites, three showed excellent diagnostic performance for distinguishing AAA patients from healthy controls. The involvement of D-amino acid metabolism suggests that perturbations in amino acid homeostasis may contribute to AAA pathogenesis alongside oxidative stress and inflammatory processes. These findings support the potential of metabolomics, including D-amino acid-related pathways, for the discovery of novel biomarkers and therapeutic targets for abdominal aortic aneurysm.

A machine learning approach to metabolomics identifies putative biomarker candidates and dysregulated pathways for distinguishing gout from asymptomatic hyperuricemia in the Zhuang population

Wei Y, Qiu X, Su L, Tang X, Chen Y, Liu S, Huang D, Zeng X, Xie Y

Metabolomics. 2026 Jul 11;22(4):124. doi: 10.1007/s11306-026-02501-w

This targeted metabolomics study investigated the metabolic transition from hyperuricemia to gout and identified sex-specific metabolic alterations associated with disease progression. In male patients, dysregulated pathways included nitrogen, purine, and D-amino acid metabolism, suggesting that metabolic changes extend beyond uric acid accumulation. Machine learning models based on selected metabolites accurately distinguished gout from both healthy controls and hyperuricemic individuals, highlighting their potential as diagnostic biomarkers. The involvement of D-amino acid metabolism underscores its possible contribution to gout pathogenesis and supports further investigation of D-amino acid-related pathways as targets for biomarker discovery and mechanism-based therapeutic strategies.

Multi-Omics Reveals Dysregulation of the Endosome-Lysosome-Autophagy Axis and Immune-Inflammatory Imbalance in Elderly Sepsis

Gou Y, Xia Z, Haireti N, Aikepaer A, Yang J, Li D

Clin Interv Aging. 2026 May 26;21:613629. doi: 10.2147/CIA.S613629

This integrative metabolomics and proteomics study identified molecular signatures specific to elderly sepsis, including the D-aspartic acid and several proteins associated with immune regulation and cellular homeostasis. Pathway analysis revealed significant alterations in D-amino acid metabolism, alanine–aspartate–glutamate metabolism, and glycerophospholipid metabolism, suggesting profound metabolic dysregulation in elderly patients with sepsis. These changes were associated with disturbances in the endosome–lysosome–autophagy axis and immune-inflammatory imbalance. The findings highlight D-amino acid metabolism as a potential contributor to the unique pathophysiology of elderly sepsis and a promising target for future biomarker and therapeutic research.

Biomolecular and cellular chirality: Novel diagnostic perspectives for diseases

Guo X, Zheng Y, Zhang W, Yao H

APL Bioeng. 2026 May 21;10(2):021504. doi: 10.1063/5.0323602

This review discusses the fundamental role of chirality in biological systems and its relevance to human health and disease. It highlights that, although low physiological levels of D-amino acids contribute to normal processes such as neurotransmission, their excessive accumulation is associated with disorders including Alzheimer’s disease, chronic kidney disease, diabetes, and aging. The review also emphasizes that disturbances in molecular and cellular chirality can promote genomic instability and tissue dysfunction. Overall, it identifies D-amino acids and other chirally altered biomolecules as promising biomarkers for the early diagnosis of a wide range of diseases.

D-Amino Acids in Human Health and Disease: Dual Functions, Metabolic Regulation, and Therapeutic Potential

Shimoda M, Hiraoka BY

BioChem, (2026) 6 (2), art. no. 10. doi: 10.3390/biochem6020010

This review provides a comprehensive overview of the sources, metabolism, and biological functions of D-amino acids in humans, highlighting their emerging roles in physiology and disease. D-amino acids such as D-serine, Daspartate, and D-alanine originate from the diet, gut microbiota, and endogenous racemization, and actively participate in neurotransmission, host–microbe interactions, and renal function. The review emphasizes their concentration-dependent effects, with physiological levels supporting normal biological processes and excessive accumulation contributing to pathological conditions. Overall, it identifies D-amino acids as multifunctional biomolecules with strong potential as diagnostic biomarkers and therapeutic targets, while underscoring the need for further research on their tissue-specific regulation and microbiota-dependent metabolism.

ENZYMES ACTIVE ON D-AAs:

A novel NADP+-dependent meso-diaminopimelate dehydrogenase from Candidatus syntrophocurvum alkaliphilum: a promising biocatalyst for D-amino acid production

Akita H, Hasegawa R, Komoriya T

FEMS Microbiol Lett. 2026 Jul 20:fnag083. doi: 10.1093/femsle/fnag083

This study describes the identification and characterization of a novel NADP⁺-dependent meso-diaminopimelate dehydrogenase (CSaDAPDH) from Candidatus Syntrophocurvum alkaliphilum with broad substrate specificity for D-amino acid synthesis. Besides catalyzing oxidative deamination of meso-diaminopimelate, the enzyme efficiently performs reductive amination of several 2-oxo acids, producing the corresponding D-amino acids. Notably, CSaDAPDH exhibits an unusually low optimum pH for reductive amination and good thermal and pH stability, making it an attractive biocatalyst for industrial applications. These findings expand the toolbox of enzymes available for the efficient and sustainable production of D-amino acids, which are increasingly important for pharmaceutical and biotechnological applications.

Crystallographic analysis of a putative FAD-dependent oxidoreductase identifies a potentially misfolded apo structure in a soluble monomeric state

Xu J, Han L, Qi H, Han Y, Chen B, Ju Y, Zhou H

J Struct Biol. 2026 May 27;218(3):108331. doi: 10.1016/j.jsb.2026.108331

This study reports the crystal structure of a misfolded form of CT375, a putative D-amino acid dehydrogenase from Chlamydia trachomatis, providing a rare example of a stable misfolded protein. Although CT375 normally binds the FAD cofactor, structural analysis revealed an abnormal apo conformation in which a misfolded loop occupies the active site, preventing cofactor binding and stabilizing the inactive structure. These findings demonstrate the essential role of FAD in the correct folding of this D-amino acid-metabolizing enzyme and provide new insights into the mechanisms of protein misfolding and cofactor-dependent protein stability.

D-AAs AND BIOTECHNOLOGY:

One-step immobilization of mutant TvDAAO yields an active and stable biocatalyst in extreme conditions

Atroshenko DL, Vlasova MA, Shelomov MD, Pometun AA, Savin SS, Tishkov VI

Bioprocess Biosyst Eng. 2026 Jul 13. doi: 10.1007/s00449-026-03386-8

Substrate-Oriented Channel Engineering of D-Amino Acid Oxidase for Efficient L/D-Phosphinothricin Resolution: Synergies of Geometric and Electrostatic Modifications

Li M, Fu C, Zhuang W, Zhang K, Xu J, Wang Z

J Agric Food Chem. 2026 Jul 16. doi: 10.1021/acs.jafc.5c15958

This study reports the rational engineering of D-amino acid oxidase (DAAO) to improve the biocatalytic production of optically pure L-phosphinothricin from D-phosphinothricin. By combining geometric remodeling of the active site with charge engineering, the authors generated a triple mutant displaying markedly enhanced substrate affinity and a 380-fold increase in catalytic efficiency. Molecular dynamics simulations revealed that optimization of both substrate tunnel geometry and the electrostatic microenvironment underlies the improved enzyme performance. These findings demonstrate an effective strategy for engineering D-amino acidmetabolizing enzymes, facilitating the efficient industrial production of valuable chiral amino acid derivatives.

Bioactive Hydrogels with D-Amino Acid RGD Mimics: A Therapeutic Strategy for Expeditious Infected Wound Closure

Negi A, Yadav S, Jain M, Goel R, Gautam HK, Singh VP, Dhawan G, Singh SK, Sharma AK, Kumar P

Adv Healthc Mater. 2026 Jul 1:e71401. doi: 10.1002/adhm.71401

This study describes the development of injectable peptide hydrogels containing D-amino acid and D/L-hybrid analogs for wound-healing applications. Increasing the D-amino acid content enhanced proteolytic resistance, antimicrobial activity against MRSA, and tissue regeneration, with the AN2D3 peptide showing the best overall performance. Molecular docking also suggested strong interaction with integrin αvβ3, supporting its role in promoting cell adhesion and proliferation. These findings demonstrate that D-amino acid incorporation is an effective strategy to improve the stability, antimicrobial efficacy, and regenerative properties of peptide-based biomaterials for advanced wound healing.

Synergistic antibacterial effect of CATH-2 and D-amino acids against mastitis causing Gram-positive bacteria

Veldhuizen EJA, van der Velden ST, Alons D, Benedictus L, van der Drift I, Ludwig IS, Schreutelkamp DE, Wösten MMSM

Front Cell Infect Microbiol. 2026 May 29;16:1819326. doi: 10.3389/fcimb.2026.1819326

This study demonstrates that combining the antimicrobial peptide CATH-2 with positively charged D-amino acids, particularly D-arginine, produces strong synergistic antibacterial activity against multidrug-resistant Staphylococcus aureus. The combination remained highly effective in both laboratory media and raw milk while showing no detectable cytotoxicity toward bovine epithelial cells. These findings highlight the potential of Damino acids to enhance the efficacy of antimicrobial peptides, offering a promising antibiotic-sparing strategy for the treatment of resistant bacterial infections such as bovine mastitis.

A biomimetic cascade nanoplatform for synergistic biofilm eradication and immune activation against MRSA

Liao C, Liao J, Nie X, Chang Q, Chen K, Zhong Z, Tang H, Wang D

RSC Adv. 2026 Jul 7. doi: 10.1039/d6ra03800j5

Discovery of a Novel Tripeptide Linker that Broadens the Therapeutic Window of
Auristatin-Based Antibody-Drug Conjugates by Reducing Bone Marrow Toxicity

Bindman NA, Magunda F, Kumar V, Rekers NV, Ortiz DJ, Trueblood ES, Blackburn S, Yumul R, Awasthi D, Caspary K, Farr L, Neace C, Anderson S, Drouhard B, Zhang X, Rincon-Arano H, Levengood MR, Okeley NM, Senter PD

Bioconjug Chem. 2026 Jul 23. doi: 10.1021/acs.bioconjchem.6c00234

Vedotin-based antibody–drug conjugates (ADCs) are highly effective but are often limited by hematologic toxicity caused by premature extracellular cleavage of the Val–Cit linker in the bone marrow. This study identified a tumor-selective tripeptide linker containing the D-amino acid D-leucine (D-Leu-Ala-Glu), which is more resistant to neutrophil proteases while maintaining efficient intracellular drug release. Incorporation of the D-amino acid significantly reduced bone marrow toxicity in preclinical models without compromising antitumor efficacy. These findings demonstrate that D-amino acids can enhance linker stability and protease selectivity, thereby improving the therapeutic index and safety profile of MMAE-based ADCs.

D-AAs IN BACTERIA:

Activity-guided discovery of antibiotic-transforming bacteria from environmental microbiomes using D-amino acid-assisted fluorescenceactivated cell sorting

Liu Y, Wang KL, Hong YQ, Yuan Y, Wang H, Chen YQ, Yu SS, Lu ZX, Pan Y, Zhu TT

Environ Pollut. 2026 Sep 15;405:128591. doi: 10.1016/j.envpol.2026.128591

This study presents an activity-guided screening strategy that combines fluorescent D-amino acid metabolic labeling with fluorescence-activated cell sorting (HADA-FACS) to isolate metabolically active bacteria from complex environmental microbiomes. Using fluorescent D-amino acids as metabolic probes, the authors identified a previously overlooked Pandoraea strain capable of transforming ciprofloxacin. Genomic and transcriptomic analyses revealed adaptive responses associated with transport, stress resistance, and redox metabolism during antibiotic exposure. These findings demonstrate that fluorescent D-amino acids are powerful tools for single-cell activity profiling, enabling the discovery of environmentally relevant microorganisms with potential applications in bioremediation.

Elucidation of D-amino acid metabolic activity of ornithine decarboxylase from the hyperthermophile Thermotoga maritima

Nogawa K, Miyamoto T

Extremophiles. 2026 Jun 30;30(1):23. doi: 10.1007/s00792-026-01435-4

This study investigated the metabolism of basic D-amino acids (D-AAs) in the hyperthermophilic bacterium Thermotoga maritima by characterizing ornithine decarboxylase (TM1873). Although the enzyme preferentially catalyzed the decarboxylation of L-ornithine and L-lysine, it also exhibited measurable activity toward Dornithine and D-lysine, indicating a previously unrecognized capacity to metabolize basic D-AAs. A second enzyme, diaminopimelate decarboxylase, showed only minimal activity toward these D-AAs. These findings provide new insights into D-AA metabolism in T. maritima and suggest that basic D-AAs may have physiological roles beyond their established function in peptidoglycan biosynthesis.

Perspective Approaches to “Trojan Horse” Strategy Development for Combating Bacterial Pathogens

Shleeva M, Kozobkova N, Demina G, Kaprelyants A

Pharmaceuticals (Basel). 2026 Apr 29;19(5):701. doi: 10.3390/ph19050701

This systematic review highlights bacterial transport systems as promising targets for “Trojan Horse” drug delivery strategies to improve the selectivity and efficacy of antibacterial therapies. Among the bacterial-specific uptake pathways examined, D-amino acid transport and metabolism are identified as attractive platforms for delivering antibiotics, photosensitizers, and diagnostic probes directly into bacterial cells. By exploiting these unique pathways, D-amino acid-based conjugates have the potential to enhance antimicrobial uptake, overcome resistance mechanisms, and reduce off-target toxicity. Overall, the review emphasizes D-amino acids as valuable components of next-generation targeted antimicrobial delivery systems, while underscoring the need to overcome key translational challenges for clinical application.

D-AAs IN PEPTIDES AND PROTEINS:

From Innate Immunity to Cancer Therapy: Antimicrobial Peptides as Emerging
Anticancer Agents

Raut N, Vohra S, Kaushalye P, Mane S, Malode D, Umekar M, Alhudhaibi AM, Chaudhary AA, Trivedi R

Int J Mol Sci. 2026 Jun 8;27(12):5179. doi: 10.3390/ijms27125179

This review summarizes the current advances in the development of antimicrobial and anticancer peptides (AMPs/ACPs) as novel cancer therapeutics. Among the engineering strategies discussed, D-amino acid substitution emerges as a key approach to enhance peptide stability, bioavailability, and resistance to proteolytic degradation while preserving anticancer activity. Combined with modifications such as cyclization, PEGylation, and nanocarrier-based delivery, D-amino acids contribute to improving the therapeutic potential of peptide-based drugs. Overall, the review highlights D-amino acid engineering as an important strategy for accelerating the clinical translation of peptide therapeutics with improved efficacy and pharmacological properties.

Chirality Effect on Physical and Biological Properties of Peptide-Based Hydrogels

De Rosa L, D’Andrea LD, Romanelli A

Gels. 2026 May 5;12(5):399. doi: 10.3390/gels12050399

This review examines how peptide chirality influences self-assembly and hydrogel formation, comparing systems composed of all L-amino acids, all D-amino acids, mixed-chirality peptides, and L/D peptide mixtures. The authors discuss how D-amino acid incorporation affects supramolecular organization, mechanical properties, and stability, often enhancing resistance to enzymatic degradation while preserving self-assembly. The review also highlights the impact of chirality on the biological performance of peptide hydrogels, including their potential applications in drug delivery, tissue engineering, and regenerative medicine. Overall, it underscores D-amino acids as key structural elements for designing robust peptide-based biomaterials with improved functional properties.

Optimized LL-37-Derived Peptides Exhibit Antitubercular Activity, Induce Membrane Disruption, and P-Type ATPase Transcriptional Responses in Mycobacterium tuberculosis

Santos PA, Maya-Hoyos M, Salazar LM, Cruz CA, Cruz-Cacais A, Giraldo-Avila M, Gómez- Manchego J, Triana LV, Soto CY

Biomolecules. 2026 Apr 30;16(5):665. doi: 10.3390/biom16050665

This study evaluates two engineered LL-37-derived antimicrobial peptides against Mycobacterium tuberculosis, demonstrating that the variant containing a single D-amino acid substitution (D-LL37) exhibits superior antimycobacterial activity compared with the parent peptide. D-amino acid incorporation enhanced peptide efficacy while promoting bacterial membrane disruption and triggering stress responses related to ion transport. Ultrastructural and gene expression analyses confirmed that D-LL37 compromises cell envelope integrity, contributing to its increased antibacterial potency. These findings highlight D-amino acid substitution as an effective strategy to optimize antimicrobial peptides for the treatment of tuberculosis, including infections caused by drug-resistant strains.

Beyond proteolysis: rational modification of mucin-derived peptidomimetics with enhanced metal-mediated antimicrobial activity

Ślusarczyk A, Bellotti D, Leveraro S, Janek T, Zobi F, Remelli M, Wątły J

RSC Adv. 2026 Jul 9. doi: 10.1039/d6ra02768g

This study investigated D-amino acid-containing peptidomimetics derived from mucin peptides and their Cu(II) and Zn(II) complexes as improved antimicrobial agents. Although D-amino acid substitution caused only minor structural changes, it markedly enhanced proteolytic stability and antimicrobial activity. The fully D-configured analogue showed the highest antibacterial and antifungal potency while remaining largely resistant to plasma degradation and exhibiting minimal cytotoxicity. Metal coordination with Cu(II) or Zn(II) further improved antimicrobial performance. These findings demonstrate that D-amino acid incorporation, particularly when combined with metal complexation, is an effective strategy to enhance the stability and therapeutic potential of antimicrobial peptides.

Structure-Activity Relationship Study of Antimicrobial Peptide with Cross-Kingdom Activity

Palakkurussi Rathessan A, Ghazisaeedi F, Unmesh K, Bingül PK, Kupke J, Chowdhary S, Hanke, Mroginski MA, Fulde M, Koksch B

Biochemistry. 2026 Jun 16;65(12):1944-1956. doi: 10.1021/acs.biochem.6c00195

This study explores structural modifications of the antimicrobial peptide SAJO-2 to improve its stability against enzymatic degradation while maintaining antimicrobial activity. Among the strategies investigated, D-amino acid incorporation played a central role in enhancing proteolytic resistance, together with β-backbone modifications and the introduction of a pentafluorinated amino acid. Although antimicrobial potency varied depending on the target microorganism, all modified peptides displayed markedly improved enzymatic stability. These findings highlight D-amino acid substitution as an effective approach to optimize peptide-based antimicrobials by increasing their durability without substantially compromising biological activity.

Structure-Activity Analysis of the Competence Stimulating Peptide-1 in Streptococcus mitis

Yeager MM, Murray AK, Bhowmic RC, Renshaw CP, Milly TA, Tal-Gan Y

ACS Infect Dis. 2026 Jul 18. doi: 10.1021/acsinfecdis.6c00548

This study investigates the structure–activity relationship of the competence-stimulating peptide (CSP1) that regulates quorum sensing in Streptococcus mitis, an emerging opportunistic pathogen. By combining alanine and D-amino acid scanning, the authors identified key residues involved in ComD1 receptor activation and demonstrated that side-chain orientation strongly influences peptide activity. The D-amino acid substitutions provided valuable insights into receptor–ligand interactions, revealing structural features essential for quorum sensing signaling. These findings support the rational design of peptide-based quorum sensing modulators and highlight the utility of D-amino acid scanning as a powerful tool for studying peptide–receptor interactions and developing anti-virulence strategies against bacterial pathogens.

Stereochemical Control of Cu(II) and Zn(II) Binding in Clavanin C Peptidomimetics

Gawłowski J, Dziadas M, Mikołajczyk-Tarnawa A, Kola A, Valensin D, Matera-Witkiewicz A, Rowińska-Żyrek M

Inorg Chem. 2026 Jul 13;65(27):15845-15854. doi: 10.1021/acs.inorgchem.6c02172

This study redesigns the antimicrobial peptide clavanin C through D-amino acid substitution and retro-inverso engineering to generate proteolytically stable metallopeptidomimetics. Both stereochemical variants retained their ability to bind Cu²⁺ and Zn²⁺ while exhibiting markedly enhanced resistance to enzymatic degradation. The retro-inverso analogue showed particularly strong activity against methicillin-resistant Staphylococcus aureus (MRSA) without detectable cytotoxicity toward mammalian cells. These findings demonstrate that D-amino acid incorporation and retro-inverso design are effective strategies for preserving metal-binding functionality and antimicrobial activity while substantially improving peptide stability, supporting the development of nextgeneration antimicrobial metallopeptides.

The D-enantiomer of the antimicrobial peptide KLKLLLLLKLK-NH(2) preferentially binds to lipopolysaccharide assemblies stabilized by divalent cations

Sato S, Kawasaki K

Biochem Biophys Res Commun. 2026 Sep 3;829:154186. doi: 10.1016/j.bbrc.2026.154186

This study demonstrates that the enhanced antimicrobial activity of the all-D antimicrobial peptide DL5 is not solely due to its resistance to proteolytic degradation but also to stereoselective interactions with bacterial lipopolysaccharide (LPS). Compared with its L-enantiomer, DL5 exhibited significantly stronger and more stable binding to LPS, particularly when the outer membrane was stabilized by divalent cations. These findings reveal that D-amino acid incorporation can improve antimicrobial efficacy by promoting specific interactions with bacterial surface structures, providing a new mechanistic basis for the superior activity of D-peptides against Gram-negative pathogens.

Metallo-beta-lactamase α-helix fragment modified peptide N10 is a multifunctional antimicrobial peptide

Lu H, Zhang Z, Zhao F, Lu W

Microbiol Spectr. 2026 Jul 17:e0304025. doi: 10.1128/spectrum.03040-25

This study describes the development of the antimicrobial peptide N10 by converting an α-helix fragment of a metallo-β-lactamase into a peptide containing D-amino acid substitutions. The resulting peptide exhibited potent antibacterial activity against carbapenem-resistant bacteria, inducing membrane disruption while also reducing oxidative stress and inflammatory responses in infected cells. Importantly, N10 showed minimal cytotoxicity and demonstrated significant therapeutic efficacy in a mouse infection model. These findings highlight the value of D-amino acid modification as an effective strategy to enhance peptide stability and therapeutic performance, supporting the development of novel antimicrobial agents to combat antibioticresistant pathogens.

Design of New Potent, Selective, and Long-Acting NOP Receptor Agonists through Multiple Sequential D-Amino Acid Substitutions of [Arg(14) Lys(15)]N/OFQ(1-15)-NH(2)

Sturaro C, Rizzo A, Morrone E, Marzola E, Pola P, Frezza A, Argentieri M, Agosta F, Ciancetta A, Preti D, Pacifico S, Albanese V, Meneguzzo G, Malfacini D, Ruzza C, Calò G, Guerrini R

J Med Chem. 2026 Jul 23. doi: 10.1021/acs.jmedchem.6c01281

This study investigated the use of multiple D-amino acid substitutions to enhance the metabolic stability of peptide agonists targeting the nociceptin/orphanin FQ (NOP) receptor. The results showed that the receptor tolerates several D-amino acid replacements within the peptide’s C-terminal region, leading to analogues with improved resistance to enzymatic degradation while maintaining full agonist activity and receptor selectivity. In particular, the optimized analogue containing multiple D-amino acids exhibited prolonged pharmacological effects in vivo, comparable to those of a well-established long-acting NOP agonist. These findings demonstrate that the strategic incorporation of D-amino acids is an effective approach for designing peptide-based NOP receptor ligands with enhanced stability and extended duration of action.

Aquatic-derived antimicrobial peptides and their strategically modified analogues as prospective anticancer therapeutics: a comprehensive systematic review of enhancement methodologies and mechanistic insights

Wekalao J, Topisia T

Front Chem. 2026 Jul 7;14:1876776. doi: 10.3389/fchem.2026.1876776

Aquatic-derived antimicrobial peptides (AMPs) represent a promising class of anticancer agents with mechanisms of action that differ from conventional chemotherapeutics, offering the potential to overcome multidrug resistance. This review highlights chemical and structural modification strategies aimed at improving peptide stability, selectivity, and bioavailability, with particular emphasis on D-amino acid substitution. Incorporation of D-amino acids enhances resistance to proteolytic degradation while preserving or improving anticancer activity, thereby increasing the therapeutic potential of AMP-based drugs. The review identifies D-amino acid engineering as a key strategy, alongside cyclization and nanoparticle conjugation, for the development of next-generation peptide therapeutics with improved pharmacological properties.

D-AAs AND ANALYTICAL METHODS (AND FOODS):

Development of a liquid chromatography-ion mobility-mass spectrometry method for the screening of D-amino acid alterations in plasma

Bogos LG, Pralea IE, Potra AR, Kacso IM, Moldovan RC, Iuga CA

J Chromatogr A. 2026 Jul 16;1785:467278. doi: 10.1016/j.chroma.2026.467278

This study presents a robust LC-ion mobility-mass spectrometry (LC-IM-MS) method for the simultaneous analysis of all proteinogenic D-amino acids in human plasma using commercially available reagents. By combining (S)-NIFE derivatization with optimized chromatographic separation, the method achieved baseline resolution of all amino acid enantiomers within 20 minutes. Application to plasma samples from patients with chronic kidney disease revealed significantly elevated levels of several D-amino acids, including D-proline, D-arginine, Dserine, D-asparagine, D-glutamine, and D-alanine. These findings demonstrate the utility of this analytical workflow for comprehensive D-amino acid profiling and support the potential of D-amino acids as biomarkers of chronic kidney disease.

Integrating State-of-the-Art Sensing Platforms for D-Amino Acid Detection: A Comprehensive Review

Cheng X, Liu M, Qin J, Wu Q, Wang D, Wei L

Anal Chem. 2026 Jul 13. doi: 10.1021/acs.analchem.6c02553

This comprehensive review examines the latest sensor‑based technologies for D-AAs detection. A central theme is the integration of engineered enzymes such as DAAO with chiral nanomaterials to enhance sensitivity and enantiomeric selectivity. Emerging electrochemical microbiosensors show particular promise for real‑time monitoring of D‑serine in neural systems. Optical and colorimetric approaches, meanwhile, offer portable solutions for food safety and clinical screening. Despite current challenges—enzyme instability, matrix interference, and limited reproducibility—the review outlines a clear roadmap toward next‑generation, miniaturized, AI‑assisted sensing platforms. Overall, it provides an essential reference for researchers aiming to translate D‑amino acid profiling into practical biomedical and diagnostic applications.

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