Self-assembly and condensation of intermolecular poly(UG) RNA quadruplexes.

Poly(UG) or 'pUG' dinucleotide repeats are highly abundant sequences in eukaryotic RNAs. In Caenorhabditis elegans, pUGs are added to RNA 3' ends to direct gene silencing within Mutator foci, a germ granule condensate. Here, we show that pUG RNAs efficiently self-assemble into gel condensates through quadruplex (G4) interactions. Short pUG sequences form right-handed intermolecular G4s (pUG G4s), while longer pUGs form left-handed intramolecular G4s (pUG folds). We determined a 1.05 Å crystal structure of an intermolecular pUG G4, which reveals an eight stranded G4 dimer involving 48 nucleotides, 7 different G and U quartet conformations, 7 coordinated potassium ions, 8 sodium ions and a buried water molecule. A comparison of the intermolecular pUG G4 and intramolecular pUG fold structures provides insights into the molecular basis for G4 handedness and illustrates how a simple dinucleotide repeat sequence can form complex structures with diverse topologies.

The barley lectin, horcolin, binds high-mannose glycans in a multivalent fashion, enabling high-affinity, specific inhibition of cellular HIV infection.

N-Linked glycans are critical to the infection cycle of HIV, and most neutralizing antibodies target the high-mannose glycans found on the surface envelope glycoprotein-120 (gp120). Carbohydrate-binding proteins, particularly mannose-binding lectins, have also been shown to bind these glycans. Despite their therapeutic potency, their ability to cause lymphocyte proliferation limits their application. In this study, we report one such lectin named horcolin (Hordeum vulgare lectin), seen to lack mitogenicity owing to the divergence in the residues at its carbohydrate-binding sites, which makes it a promising candidate for exploration as an anti-HIV agent. Extensive isothermal titration calorimetry experiments reveal that the lectin was sensitive to the length and branching of mannooligosaccharides and thereby the total valency. Modeling and simulation studies demonstrate two distinct modes of binding, a monovalent binding to shorter saccharides and a bivalent mode for higher glycans, involving simultaneous interactions of multiple glycan arms with the primary carbohydrate-binding sites. This multivalent mode of binding was further strengthened by interactions of core mannosyl residues with a secondary conserved site on the protein, leading to an exponential increase in affinity. Finally, we confirmed the interaction of horcolin with recombinant gp120 and gp140 with high affinity and inhibition of HIV infection at nanomolar concentrations without mitogenicity.

Recuperative potential of Indian medicinal plant compounds- a tool to encumber henipaviruses: an in -silico study.

Henipaviruses, highly fatal zoonotic viruses with mortality rates up to 100%, pose a significant threat to humans. Despite sporadic cases, including infections from Cedar, Langya, and Nipah Viruses, there are no established drugs or vaccines for treatment. This lack of specific medication led us to explore 57 non-toxic compounds from Indian Medicinal Plants, selected from 232 compounds, aiming to combat these viruses. Through in silico ADMET analyses, Three compounds-andrographolide, pterygospermin and Salidroside-stood out for their exceptional non-toxic properties. These compounds underwent in silico target prediction, molecular docking and dynamics with Cedar, Langya, and Nipah Virus proteins from the Protein Data Bank. Among them, Andrographolide displayed the most promising negative free energy scores and stability in Cedar Virus-Attachment G-Protein binding pockets. Pterygospermin and Salidroside showed efficacy against Langya and Nipah Virus target proteins throughout the simulation. These compounds not only exhibited antiviral properties but also demonstrated immunomodulatory, anti-inflammatory, and hepatoprotective effects by our in-silico studies. Their potential as treatments or preventive measures against henipaviral infections makes them promising candidates for further research and development. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00236-x.

An atypical RNA quadruplex marks RNAs as vectors for gene silencing.

The addition of poly(UG) ('pUG') repeats to 3' termini of mRNAs drives gene silencing and transgenerational epigenetic inheritance in the metazoan Caenorhabditis elegans. pUG tails promote silencing by recruiting an RNA-dependent RNA polymerase (RdRP) that synthesizes small interfering RNAs. Here we show that active pUG tails require a minimum of 11.5 repeats and adopt a quadruplex (G4) structure we term the pUG fold. The pUG fold differs from known G4s in that it has a left-handed backbone similar to Z-RNA, no consecutive guanosines in its sequence, and three G quartets and one U quartet stacked non-sequentially. The compact pUG fold binds six potassium ions and brings the RNA ends into close proximity. The biological importance of the pUG fold is emphasized by our observations that porphyrin molecules bind to the pUG fold and inhibit both gene silencing and binding of RdRP. Moreover, specific 7-deaza substitutions that disrupt the pUG fold neither bind RdRP nor induce RNA silencing. These data define the pUG fold as a previously unrecognized RNA structural motif that drives gene silencing. The pUG fold can also form internally within larger RNA molecules. Approximately 20,000 pUG-fold sequences are found in noncoding regions of human RNAs, suggesting that the fold probably has biological roles beyond gene silencing.

Jellyfish venom proteins and their pharmacological potentials: A review.

Several research in the organisms of marine invertebrates to assess the medicinal ability of its bio-active molecules have yielded very positive results in recent times. Jellyfish secreted venoms are rich sources of toxins intended to catch prey or deter predators among invertebrate species, but they may also have harmful effects on humans. The nematocyst, a complex intracellular system that injects a venomous mixture into prey or predators that come into contact with the tentacles or other parts of the body of cnidarians, determines the venomous existence of cnidarians. Nematocyst venoms are mixtures of peptides, proteins and other components that in laboratory animals can induce cytotoxicity, blockade of ion channels, membrane pore formation, in vivo cardiovascular failure and lethal effects. There are also valuable pharmacological and biological aspects of jellyfish venoms. In the present review, overviews of the variety of possible toxin families in cnidarian venoms are addressed in this analysis and these potential toxins are surveyed with those from other cnidarians that offer insight into their potential functions such as anti-oxidant, anti-cancer activity and much more. This research review will provide awareness of the growing repertoire of jellyfish venom proteins and will help to further isolate and classify particular proteins to understand its structure and functional relationship.

Linkages between oral commensal bacteria and atherosclerotic plaques in coronary artery disease patients.

Coronary artery disease is an inflammatory disorder characterized by narrowing of coronary arteries due to atherosclerotic plaque formation. To date, the accumulated epidemiological evidence supports an association between oral bacterial diseases and coronary artery disease, but has failed to prove a causal link between the two. Due to the recent surge in microbial identification and analyses techniques, a number of bacteria have been independently found in atherosclerotic plaque samples from coronary artery disease patients. In this study, we present meta-analysis from published studies that have independently investigated the presence of bacteria within atherosclerotic plaque samples in coronary artery disease patients. Data were collated from 63 studies covering 1791 patients spread over a decade. Our analysis confirms the presence of 23 oral commensal bacteria, either individually or in co-existence, within atherosclerotic plaques in patients undergoing carotid endarterectomy, catheter-based atherectomy, or similar procedures. Of these 23 bacteria, 5 (Campylobacter rectus, Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia, Prevotella nigrescens) are unique to coronary plaques, while the other 18 are additionally present in non-cardiac organs, and associate with over 30 non-cardiac disorders. We have cataloged the wide spectrum of proteins secreted by above atherosclerotic plaque-associated bacteria, and discuss their possible roles during microbial migration via the bloodstream. We also highlight the prevalence of specific poly-microbial communities within atherosclerotic plaques. This work provides a resource whose immediate implication is the necessity to systematically catalog landscapes of atherosclerotic plaque-associated oral commensal bacteria in human patient populations.