Institut Pasteur Korea

A screen of ~ 4000 actinomycetes strains identified Streptomyces sp. W3009 as a producer of the antituberculosis agent pyridomycin. Using a mass spectrometry-based metabolomics approach coupled with molecular networking, we identified seven pyridomycin derivatives, six of which were novel. Three of these novel compounds were linear, featuring a unique 3-hydroxypicolinic acid–l-threonine–3-(3-pyridyl)-l-alanine (3HP–T–3PA) scaffold. Their structures were elucidated via detailed NMR studies. While two cyclic derivatives (4 and 5) showed modest antitubercular activity, the three linear derivatives, despite possessing the key 3HP–T–3PA moiety, exhibited no inhibitory activity. This intensive MS-based approach demonstrates the important role of such techniques in the discovery of novel biologically active core structures and their natural derivatives.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s13659-025-00576-x.

Abstract Description Squalene-based emulsion (SE) adjuvants like MF59 and AS03 are used in protein subunit vaccines against influenza virus and SARS-CoV-2. We demonstrate the critical role of uric acid (UA), a damage-associated molecular pattern (DAMP), in triggering immunogenicity by SE adjuvants. In mice, SE adjuvants elevated DAMP levels in draining lymph nodes. Strikingly, UA perturbation reduced the vaccine-induced innate immunity, to subsequently impair antibody and T cell responses. In vivo treatment with UA crystals elicited partial adjuvant effects. In vitro stimulation with UA crystals augmented the activation of dendritic cells (DCs) and B cells and altered multiple pathways in these cells, including inflammation and antigen presentation in DCs and cell proliferation in B cells. In an influenza vaccine model, UA contributed to protection against influenza viral infection. These results demonstrate the importance of DAMPs, specifically the versatile role of UA in the immunogenicity of SE adjuvants, by regulating DCs and B cells. Funding Sources Supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIT; grant number NRF-2021R1C1C1012962 and RS-2024-00398073). Topic Categories Vaccines and Immunotherapy (VAC)

The ongoing global threats posed by COVID-19 pandemic, catalyzed by SARS-CoV-2, underscores the pressing need for effective antiviral strategies. The viral non-structural protein 1 (Nsp1) significantly influences pathogenicity by impeding host protein expression and enhancing viral RNA translation through its interaction with the stem-loop 1 (SL1) in the 5' untranslated region (UTR). We have developed a novel dual-luciferase reporter assay, designed to investigate the critical Nsp1-SL1 interaction, and identified P23E02 as a potential inhibitor. Our investigation, combining molecular docking studies and alanine mutagenesis, has unveiled that P23E02 disrupts Nsp1-40S ribosomal subunit interaction, liberating translational inhibition and empowering host antiviral responses. P23E02 exhibits antiviral efficacy against various sarbecoviruses, making it a promising candidate for combatting COVID-19 and related diseases. This study underscores the therapeutic potential of targeting the Nsp1/SL1 axis and lays the foundation for innovative antiviral interventions, ultimately fortifying global preparedness against future viral threats.

Praziquantel (PZQ) is currently the only approved drug for treating clonorchiasis, but its poor efficacy against Clonorchis sinensis larvae has highlighted the need to develop newer drugs. In this study, to address this challenge, we investigated the anti-parasitic efficacy of miltefosine (MLT), curcumin (CUR), and PZQ against C. sinensis metacercariae (CsMC), newly excysted juvenile worms (CsNEJs), and adults. Larvicidal effects of MLT and CUR surpassed those elicited by PZQ in vitro. These two drugs exerted their effect against both CsMC and CsNEJs in a dose- and time-dependent manner. To confirm the effect of these drugs in vivo, Syrian golden hamsters were orally infected with 100 CsMC and subsequently treated with MLT, CUR, or PZQ at 1 and 4 weeks post-infection (wpi). MLT and CUR reduced the worm recoveries at 1 and 4 wpi, indicating that these drugs were efficacious against both larvae and adult C. sinensis. PZQ was only efficacious against adult worms. Interestingly, both MLT and CUR showed lower levels of C. sinensis-specific IgG responses than the infection control group, implying that worm burden and bile IgG responses could be correlated. These results indicate that MLT and CUR are efficacious against both larval and adult stages of C. sinensis, thereby highlighting their potential for further development as alternative therapeutic options for clonorchiasis.

The immune escape of Omicron variants significantly subsides by the third dose of an mRNA vaccine. However, it is unclear how Omicron variant-neutralizing antibodies develop under repeated vaccination. We analyze blood samples from 41 BNT162b2 vaccinees following the course of three injections and analyze their B-cell receptor (BCR) repertoires at six time points in total. The concomitant reactivity to both ancestral and Omicron receptor-binding domain (RBD) is achieved by a limited number of BCR clonotypes depending on the accumulation of somatic hypermutation (SHM) after the third dose. Our findings suggest that SHM accumulation in the BCR space to broaden its specificity for unseen antigens is a counterprotective mechanism against virus variant immune escape.

Leishmaniasis, an infectious disease caused by pathogenic Leishmania parasites, affects millions of people in developing countries, and its re-emergence in developed countries, particularly in Europe, poses a growing public health concern. The limitations of current treatments and the absence of effective vaccines necessitate the development of novel therapeutics. In this study, we focused on identifying small molecule inhibitors which prevents the interaction between peroxin 5 (PEX5) and peroxisomal targeting signal 1 (PTS1), pivotal for kinetoplastid parasite survival. The Leishmania donovani PEX5, containing a C-terminal tetratricopeptide repeat (TPR) domain, was expressed and purified, followed by the quantification of kinetic parameters of PEX5-PTS1 interactions. A fluorescence polarization-based high-throughput screening assay was developed and small molecules inhibiting the LdPEX5-PTS1 interaction were discovered through the screening of a library of 51,406 compounds. Based on the confirmatory assay, nine compounds showed half maximal inhibitory concentration (IC50) values ranging from 3.89 to 24.50 µM. In silico docking using a homology model of LdPEX5 elucidated that the molecular interactions between LdPEX5 and the inhibitors share amino acids critical for PTS1 binding. Notably, compound P20 showed potent activity against the growth of L. donovani promastigotes, L. major promastigotes, and Trypanosoma brucei blood stream form, with IC50 values of 12.16, 19.21, and 3.06 μM, respectively. The findings underscore the potential of targeting LdPEX5-PTS1 interactions with small molecule inhibitors as a promising strategy for the discovery of new anti-parasitic compounds.

A Gram-stain-positive, non-spore-forming, and obligate anaerobic bacteria designated strain CBA3647T was isolated from a horse faecal sample in Jeju, Republic of Korea. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain CBA3647T formed a distinct phyletic lineage from closely related species within the genus Peptostreptococcus. Based on comparative analysis of 16S rRNA gene sequences, Peptostreptococcus anaerobius ATCC 27337T is most closely related to strain CBA3647T with a 16S rRNA gene similarity of 98.31 %, while similarity to other type strains is below 98.0 %. The genomic DNA G+C content of strain CBA3647T was 30.0 mol%. The digital DNA-DNA hybridization values between strain CBA3647T and the six Peptostreptococcus species were equal to or less than 24 %. Cells were non-motile and oval-shaped cocci with catalase-positive and oxidase-negative activities. Growth occurred at 20-40 °C (optimum, 35 °C), pH 6-8 (optimum, pH 7), and in the presence of 0-2 % (w/v) NaCl (optimum, 1 %). Strain CBA3647T contained C14 : 0 iso and C16 : 0 as major fatty acids. Phenotypic, chemotaxonomic, and molecular properties of strain CBA3647T suggest that it represents a novel species in the genus Peptostreptococcus, which has been named Peptostreptococcus equinus sp. nov. The type strain is CBA3647T (=KACC 22891T= JCM 35846T).

To develop a universal coronavirus (CoV) vaccine, long-term immunity against multiple CoVs, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, Middle East respiratory syndrome (MERS)–CoV, and future CoV strains, is crucial. Following the 2015 Korean MERS outbreak, we conducted a long-term follow-up study and found that although neutralizing antibodies and memory T cells against MERS-CoV declined over 5 years, some recovered patients exhibited increased antibody levels during the COVID-19 pandemic. This likely resulted from cross-reactive immunity induced by SARS-CoV-2 vaccines or infections. A significant correlation in antibody responses across various CoVs indicates shared immunogenic epitopes. Two epitopes—the spike protein’s stem helix and intracellular domain—were highly immunogenic after MERS-CoV infection and after SARS-CoV-2 vaccination or infection. In addition, memory T cell responses, especially polyfunctional CD4+ T cells, were enhanced during the pandemic, correlating significantly with MERS-CoV spike-specific antibodies and neutralizing activity. Therefore, incorporating these cross-reactive and immunogenic epitopes into pan-CoV vaccine formulations may facilitate effective vaccine development.