ACS Central Science最新文献

Pseudomonas aeruginosa is one of the leading causes of nosocomial infections and has become increasingly resistant to multiple antibiotics. However, development of novel classes of antibacterial agents against multidrug-resistant P. aeruginosa is extremely difficult. Herein we develop a semisynthetic oligomannuronic acid-based glycoconjugate vaccine that confers broad protection against infections of both mucoid and nonmucoid strains of P. aeruginosa. The well-defined glycoconjugate vaccine formulated with Freund’s adjuvant (FA) employing a highly conserved antigen elicited a strong and specific immune response and protected mice against both mucoid and nonmucoid strains of P. aeruginosa. The resulting antibodies recognized different strains of P. aeruginosa and mediated the opsonic killing of the bacteria at varied levels depending on the amount of alginate expressed on the surface of the strains. Vaccination with the glycoconjugate vaccine plus FA significantly promoted the pulmonary and blood clearance of the mucoid PAC1 strain of P. aeruginosa and considerably improved the survival rates of mice against the nonmucoid PAO1 strain of P. aeruginosa. Thus, the semisynthetic glycoconjugate is a promising vaccine that may provide broad protection against both types of P. aeruginosa.

A semisynthetic oligomannuronic acid-based glycoconjugate vaccine was developed to provide broad protection against infections of both mucoid and nonmucoid strains of Pseudomonas aeruginosa.

Adenosine-to-inosine (A-to-I) editing is one of the most widespread post-transcriptional RNA modifications and is catalyzed by adenosine deaminases acting on RNA (ADARs). Varying across tissue types, A-to-I editing is essential for numerous biological functions, and dysregulation leads to autoimmune and neurological disorders, as well as cancer. Recent evidence has also revealed a link between RNA localization and A-to-I editing, yet understanding of the mechanisms underlying this relationship and its biological impact remains limited. Current methods rely primarily on in vitro characterization of extracted RNA that ultimately erases subcellular localization and cell-to-cell heterogeneity. To address these challenges, we have repurposed endonuclease V (EndoV), a magnesium-dependent ribonuclease that cleaves inosine bases in edited RNA, to selectively bind and detect A-to-I edited RNA in cells. The work herein introduces an endonuclease V immunostaining assay (EndoVIA), a workflow that provides spatial visualization of edited transcripts, enables rapid quantification of overall inosine abundance, and maps the landscape of A-to-I editing within the transcriptome at the nanoscopic level.

EndoVIA detects adenosine-to-inosine editing in cells, providing spatial visualization and quantification of overall inosine abundance with nanoscale resolution.

Detoxification of heme in Plasmodium depends on its crystallization into hemozoin. This pathway is a major target of antimalarial drugs. The crystalline structure of hemozoin was established by X-ray powder diffraction using a synthetic analog, β-hematin. Here, we apply emerging methods of in situ cryo-electron tomography and 3D electron diffraction to obtain a definitive structure of hemozoin directly from ruptured parasite cells. Biogenic hemozoin crystals take a striking polar morphology. Like β-hematin, the unit cell contains a heme dimer, which may form four distinct stereoisomers: two centrosymmetric and two chiral enantiomers. Diffraction analysis, supported by density functional theory analysis, reveals a selective mixture in the hemozoin lattice of one centrosymmetric and one chiral dimer. Absolute configuration has been determined by morphological analysis and confirmed by a novel method of exit-wave reconstruction from a focal series. Atomic disorder appears on specific facets asymmetrically, and the polar morphology can be understood in light of water binding. Structural modeling of the heme detoxification protein suggests a function as a chiral agent to bias the dimer formation in favor of rapid growth of a single crystalline phase. The refined structure of hemozoin should serve as a guide to new drug development.

The polar shape of hemozoin crystals reflects the isomeric composition of the heme dimer in the unit cell.

We present orally administrable prodrugs (OSC-GCDIs) of guanidino oseltamivir carboxylate (GOC) based on guanidine cyclic diimide (GCDI) to treat influenza viruses. By concealing the guanidine group, which significantly limits the intestinal absorption, its prodrugs OSC-GCDIs demonstrate dramatic improvement of oral bioavailability. The most promising antiviral substance OSC-GCDI(P) readily forms covalent adducts with serum proteins via a degradable linker after the intestinal absorption. Subsequently, the active species, GOC, is released from the conjugate in a sustained manner, which greatly contributes to improving pharmacokinetic properties. Because of the remarkable improvements in both oral bioavailability and longevity of its active metabolite, OSC-GCDI(P) demonstrates outstanding therapeutic efficacy against both wild-type and oseltamivir-resistant (H275Y) influenza virus strains in a mouse infection model, even with a single oral administration.

Guanidine cyclic diimide-based prodrugs dramatically enhance oral bioavailability and pharmacokinetic half-life to show long-time therapeutic activity against broad-spectrum influenza viruses.