Broad-spectrum host-acting antivirals: identification and characterization of anti-HIV drugs

Fleta Soriano, Eric

Broad-spectrum host-acting antivirals: identification and characterization of anti-HIV drugs

Document Type

Doctoral thesis
Published Version

Author

Fleta Soriano, Eric

Director

Meyerhans, Andreas

Publication Date

2015-12-18

Pages

137 p.

License

Citation

Fleta Soriano, E. Broad-spectrum host-acting antivirals: identification and characterization of anti-HIV drugs. Universitat Pompeu Fabra; 2015. handle: http://hdl.handle.net/10803/402212

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

Hundreds of host factors related to viral infections like HIV, hepatitis C virus, dengue virus or West Nile virus have been identified. As many of these host factors are shared by different viruses, chemical blockade of key virus-associated cellular components may effectively act as broad-spectrum antiviral treatment. Broad-spectrum host-acting antivirals (HAAs) may reduce treatment complexity and costs, increase adherence to the therapy and may pose a higher barrier to develop resistance. In this thesis a high-throughput anti-HIV assay was used to screen for virus inhibitory effects of a library of secondary metabolites derived from myxobacteria. Compounds with high anti-HIV activity and low toxicity were classified as hits and two of them (ratjadone A and soraphen A) were selected for further analysis. The mechanism of HIV inhibition of both compounds is described here. The results presented in this thesis show that broad-spectrum HAAs are a feasible option for antiviral treatment and that the compounds identified can be further studied for hit-to-lead compound development.
Cientos de factores del huésped relacionados con infecciones virales por VIH, hepatitis C, dengue o virus del Nilo occidental han sido identificados. Como muchos de esos factores del huésped son compartidos por diferentes virus, el bloqueo químico de un componente celular clave asociado al virus podría actuar de forma efectiva como un tratamiento antiviral de amplio espectro. Antivirales de amplio espectro contra factores del huésped podrían reducir la complejidad y el coste del tratamiento, incrementar el cumplimiento de la terapia y pueden suponer una barrera mayor al desarrollo de resistencia. En esta tesis un cribado de alta capacidad anti-VIH fue aplicado a una librería de metabolitos secundarios de myxobacteria. Compuestos con alta actividad anti-VIH y baja toxicidad fueron clasificados como hits y dos de ellos (ratjadone A y soraphen A) fueron seleccionados para posteriores estudios. El mecanismo de inhibition de VIH de ambos compuestos es descrito aquí. Los resultados presentados en esta tesis muestran que usar antivirales de amplio espectro contra factores del huésped es un opción viable para tratamientos antivirales y que los compuestos identificados pueden ser estudiados para el desarrollo de fármacos.