Background: Mosquito odorant-binding proteins constitute molecular targets for structure-based discovery of novel hostseeking disruptors. Results: "Plus-C" AgamOBP48 exists as a three-dimensional domain-swapped dimer containing a combined binding site. Conclusion: Domain swapping has important implications for AgamOBP48 binding specificity. Significance: OBP dimerization should be considered in a successful OBP-based discovery strategy.
The bacterial ribosome represents the confirmed biological target for many known antibiotics that interfere with bacterial protein synthesis. Aminoglycosides represent a lead paradigm in RNA molecular recognition and constitute ideal starting points for the design and synthesis of novel RNA binders. Previous rational design approaches of RNA-targeting small molecules have been mainly concentrated on direct functionalization of aminoglycosidic substructures. Herein, we successfully designed and synthesized rigid spirocyclic scaffolds locked in a predicted ribosome-bound "bioactive" conformation. These analogues are able to mimic many of the interactions of the natural products for the A-site, as proven by their obtained binding affinities. The development of an optimized approach for their synthesis and their potential to inhibit protein production in vitro are presented. Our results could be further utilized for the development of analogues with improved antibiotic profiles.
Odorant-dependent behaviors in insects are triggered by the binding of odorant ligands to the variable subunits of heteromeric olfactory receptors. Previous studies have shown, however, that specific odor binding to ORco, the common subunit of odorant receptor heteromers, may allosterically alter olfactory receptor function and profoundly affect subsequent behavioral responses. Using an insect cell–based screening platform, we identified and characterized several antagonists of the odorant receptor coreceptor of the African malaria vector
Anopheles gambiae
(AgamORco) in a small collection of natural volatile organic compounds. Because some of the identified antagonists were previously shown to strongly repel
Anopheles
and
Culex
mosquitoes, we examined the bioactivities of the identified antagonists against
Aedes
, the third major genus of the Culicidae family. The tested antagonists inhibited the function of
Ae. aegypti
ORco
ex vivo
and repelled adult Asian tiger mosquitoes (
Ae. albopictus
). Binary mixtures of specific antagonists elicited higher repellency than single antagonists, and binding competition assays suggested that this enhanced repellence is due to antagonist interaction with distinct ORco sites. Our results also suggest that the enhanced mosquito repellency by antagonist mixtures is due to additive rather than synergistic effects of the specific antagonist combinations on ORco function. Taken together, these findings provide novel insights concerning the molecular aspects of odorant receptor function. Moreover, our results demonstrate that a simple screening assay may be used for the identification of allosteric modifiers of olfactory-driven behaviors capable of providing enhanced personal protection against multiple mosquito-borne infectious diseases.
Hybrid organic-inorganic (dendritic polymer-silica) xerogels containing silver nanoparticles (Ag Nps) were developed as antibacterial leather coatings. The preparation method is environmentally friendly and is based on two biomimetic reactions. Silica gelation and spontaneous Ag Nps formation were both mediated by hyperbranched poly (ethylene imine) (PEI) scaffolds of variable Mw (2000–750,000). The formation of precursor hydrogels was monitored by dynamic light scattering (DLS). The chemical composition of the xerogels was assessed by infrared spectroscopy (IR) and energy-dispersive X-ray spectroscopy (EDS), while the uniformity of the coatings was established by scanning electron microscopy (SEM). The release properties of coated leather samples and their overall behavior in water in comparison to untreated analogs were investigated by Ultraviolet-Visible (UV-Vis) spectroscopy. Antibacterial activity was tested against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, and antibiofilm properties against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Acinetobacter baumannii, and Enterococcus faecalis, while the SARS-CoV-2 clinical isolate was employed for the first estimation of their antiviral potential. Toxicity was evaluated using the Jurkat E6.1 cell line. Finally, water-contact angle measurements were implemented to determine the enhancement of the leather surface hydrophilicity caused by these composite layers. The final advanced products are intended for use in medical applications.
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