Unveiling tetrahydroquinolines as promising BVDV entry inhibitors: Targeting the envelope protein.

Bovine viral diarrhea virus (BVDV) is known to cause financial losses and decreased productivity in the cattle industry worldwide. Currently, there are no available antiviral treatments for effectively controlling BVDV infections in laboratories or farms. The BVDV envelope protein (E2) mediates receptor recognition on the cell surface and is required for fusion of virus and cell membranes after the endocytic uptake of the virus during the entry process. Therefore, E2 is an attractive target for the development of antiviral strategies. To identify BVDV antivirals targeting E2 function, we defined a binding site in silico located in domain IIIc at the interface between monomers in the disulfide linked dimer of E2. Employing a de novo design methodology to identify compounds with the potential to inhibit the E2 function, compound 9 emerged as a promising candidate with remarkable antiviral activity and minimal toxicity. In line with targeting of E2 function, compound 9 was found to block the virus entry into host cells. Furthermore, we demonstrated that compound 9 selectively binds to recombinant E2 in vitro. Molecular dynamics simulations (MD) allowed describing a possible interaction pattern between compound 9 and E2 and indicated that the S enantiomer of compound 9 may be responsible for the antiviral activity. Future research endeavors will focus on synthesizing enantiomerically pure compounds to further support these findings. These results highlight the usefulness of de novo design strategies to identify a novel class of BVDV inhibitors that block E2 function inhibiting virus entry into the host cell.

Discovery of a Potent and Selective Chikungunya Virus Envelope Protein Inhibitor through Computer-Aided Drug Design.

The worldwide expansion of chikungunya virus (CHIKV) into tropical and subtropical areas in the last 15 years has posed a currently unmet need for vaccines and therapeutics. The E2-E1 envelope glycoprotein complex binds receptors on the host cell and promotes membrane fusion during CHIKV entry, thus constituting an attractive target for the development of antiviral drugs. In order to identify CHIKV antivirals acting through inhibition of the envelope glycoprotein complex function, our first approach was to search for amenable druggable sites within the E2-E1 heterodimer. We identified a pocket located in the interface between E2 and E1 around the fusion loop. Then, via a structure-based virtual screening approach and in vitro assay of antiviral activity, we identified compound 7 as a specific inhibitor of CHIKV. Through a lead optimization process, we obtained compound 11 that demonstrated increased antiviral activity and low cytotoxicity (EC50 1.6 µM, CC50 56.0 µM). Molecular dynamics simulations were carried out and described a possible interaction pattern of compound 11 and the E1-E2 dimer that could be useful for further optimization. As expected from target site selection, compound 11 inhibited virus internalization during CHIKV entry. In addition, virus populations resistant to compound 11 included mutation E2-P173S, which mapped to the proposed binding pocket, and second site mutation E1-Y24H. Construction of recombinant viruses showed that these mutations conferred antiviral resistance in the parental background. Finally, compound 11 presents acceptable solubility values and is chemically and enzymatically stable in different media. Altogether, these findings uncover a suitable pocket for the design of CHIKV entry inhibitors with promising antiviral activity and pharmacological profiles.

Onicomicosis en paciente inmunocompetente por Aspergillus sección Candidi / Onychomycosis in immunocompetent patient by Aspergillus section Candidi

Introducción: los hongos miceliales no dermatofitos (HMND) pueden causar un gran número de infecciones, entre ellas, la onicomicosis. Su implicancia como agentes patógenos y su significado clínico en esta afección, se encuentran sujetos al cumplimiento de los criterios de Walshe y Mary P. English. Presentamos un caso de onicomicosis causada por un hongo hifomiceto poco frecuente, del género Asper-gillus sección Candidi, en una paciente inmunocompetente y su estrategia terapéutica. Materiales y métodos: se estudió una paciente inmunocompetente, de 43 años de edad, con lesión en uña de primer dedo del pie derecho, de 10 años de evolución. Se realizó toma de muestra para examen micológico. Resultados: el examen directo reveló la presencia de hifas hialinas irregulares, ramificadas y tabica-das, compatibles con HMND. En muestras seriadas, desarrollaron colonias blanco algodonosas, cuya micromorfología fue concordante con Aspergillus sección Candidi. La identificación fue confirmada en la Unidad de Micología del Hospital de Infecciosas Francisco Javier Muñiz de la Ciudad Autónoma de Buenos Aires, Argentina. Allí también se realizaron pruebas de sensibilidad a antifúngicos, resultando sensible a itraconazol y terbinafina. Conclusión: exponemos un caso de onicomicosis causada por Aspergillus sección Candidi, HMND no queratinolítico, de escasa frecuencia de aparición, siendo el primer caso descripto y publicado en Argentina. También se planteó una estrategia terapéutica efectiva, que condujera a la cura clínica y microbiológica, de la uña de la paciente.

Introduction: non-dermatophyte mycelial fungi (HMND) can cause a large number of infections, including onychomycosis. Its implica-tion as pathogens and its clinical significance in this condition are subject to compliance with Walshe's and Mary P. English's criteria. We present a case of onychomycosis caused by hyphomycete rare fungus, of the genus Aspergillus section Candidi, in an immunocompetent patient and its therapeutic strategy. Materials and methods: a 43-year-old immunocompetent patient with a 10-year-old right-toe nail lesion was studied. Samples were taken for mycological examination. Results: the direct examination revealed the presence of irregu-lar, branched and tabulated hyaline hyphae, compatible with HMND. In serial samples, they developed white cotton colonies, whose micromorphology was consistent with Aspergillus, section Candidi. The identification was confirmed at the Mycology Unit of Francisco Javier Muñiz Infectious Hospital in the Autonomous City of Buenos Aires, Argentina. Susceptibility to antifungals was also tested there, resulting in susceptibility to itraconazole and terbinafine. Conclusion: we present a case of onychomycosis caused by Aspergillus section Candidi, non-keratinolytic HMND, of rare occurrence, being the first case described and published in Argentina. An effective therapeutic strategy was also proposed that led to the patient's toenail's clinical and microbiological cure.