The neurotransmitter acetylcholine (ACh) is bound with 50-micromolar affinity by a completely synthetic receptor (host) comprising primarily aromatic rings. The host provided an overall hydrophobic binding site, but one that could recognize the positive charge of the quaternary ammonium group of ACh through a stabilizing interaction with the electron-rich pi systems of the aromatic rings (cation-pi interaction). Similar interactions may be involved in biological recognition of ACh and other choline derivatives.
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http://dx.doi.org/10.1126/science.2274786 | DOI Listing |
Mol Ther Oncol
March 2025
Early Protein Supply and Characterization, Merck Healthcare KGaA, 64293 Darmstadt, Germany.
In this work, we report the discovery and engineering of allosteric variable domains of the heavy chain (VHHs) derived from camelid immunization targeting NKp30, an activating receptor on natural killer (NK) cells. The aim was to enhance NK cell-mediated killing capacities by identifying VHHs that do not compete with the natural ligand of NKp30:B7-H6, thereby maximizing the recognition of B7-H6 tumor cells. By relying on the DuoBody technology, bispecific therapeutic antibodies were engineered, creating a panel of bispecific antibodies against NKp30xEGFR (cetuximab moiety) or NKp30xHER2 (trastuzumab moiety), called natural killer cell engagers (NKCEs).
View Article and Find Full Text PDFNat Struct Mol Biol
January 2025
Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA.
Transient receptor potential channel subfamily M member 3 (TRPM3) is a Ca-permeable cation channel activated by the neurosteroid pregnenolone sulfate (PregS) or heat, serving as a nociceptor in the peripheral sensory system. Recent discoveries of autosomal dominant neurodevelopmental disorders caused by gain-of-function mutations in TRPM3 highlight its role in the central nervous system. Notably, the TRPM3 inhibitor primidone, an anticonvulsant, has proven effective in treating patients with TRPM3-linked neurological disorders and in mouse models of thermal nociception.
View Article and Find Full Text PDFNPJ Vaccines
January 2025
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
Cyclic peptides are often used as scaffolds for the multivalent presentation of drug molecules due to their structural stability and constrained conformation. We identified a cyclic deca-peptide incorporating lipoamino acids for delivering T helper and B cell epitopes against group A Streptococcus (GAS), eliciting robust humoral immune responses. In this study, we assessed the function-immunogenicity relationship of the multi-component vaccine candidate (referred to as VC-13) to elucidate a mechanism of action.
View Article and Find Full Text PDFSignal Transduct Target Ther
January 2025
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.
The excessive cytokine release and limited persistence represent major challenges for chimeric antigen receptor T (CAR-T) cell therapy in diverse tumors. Conventional CARs employ an intracellular domain (ICD) from the ζ subunit of CD3 as a signaling module, and it is largely unknown how alternative CD3 chains potentially contribute to CAR design. Here, we obtained a series of CAR-T cells against HER2 and mesothelin using a domain comprising a single immunoreceptor tyrosine-based activation motif from different CD3 subunits as the ICD of CARs.
View Article and Find Full Text PDFExpert Opin Pharmacother
January 2025
Department of Obstetrics and Gynecology, University of Florence, Careggi University Hospital, Florence, Italy.
Introduction: Dysmenorrhea is a painful symptom associated with uterine contractions and menstrual bleeding and is treated by administering analgesic drugs. Since progesterone receptors (PRs) have a major role in regulating uterine tissues (myometrium and endometrium) oral contraceptives are used off-label for treating primary or secondary dysmenorrhea. The development of selective progesterone receptor modulators (SPRMs) a class of synthetic steroids with agonistic, antagonistic, or mixed effects in targeting PRs in different tissues stimulated their possible clinical use for treating secondary dysmenorrhea related to uterine diseases (endometriosis, adenomyosis, uterine fibroids).
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