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Rational CCL5 mutagenesis integration in a lactobacilli platform generates extremely potent HIV-1 blockers.
Secchi, Massimiliano; Grampa, Valentina; Vangelista, Luca.
Afiliação
  • Secchi M; Protein Engineering and Therapeutics Group, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132, Milan, Italy.
  • Grampa V; Protein Engineering and Therapeutics Group, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132, Milan, Italy.
  • Vangelista L; INSERM, UMRS-839, Institut du Fer à Moulin, 75005, Paris, France.
Sci Rep ; 8(1): 1890, 2018 01 30.
Article em En | MEDLINE | ID: mdl-29382912
Efforts to improve existing anti-HIV-1 therapies or develop preventatives have identified CCR5 as an important target and CCL5 as an ideal scaffold to sculpt potent HIV-1 entry inhibitors. We created novel human CCL5 variants that exhibit exceptional anti-HIV-1 features using recombinant lactobacilli (exploited for live microbicide development) as a screening platform. Protein design, expression and anti-HIV-1 activity flowed in iterative cycles, with a stepwise integration of successful mutations and refinement of an initial CCL5 mutant battery towards the generation of two ultimate CCL5 derivatives, a CCR5 agonist and a CCR5 antagonist with similar anti-HIV-1 potency. The CCR5 antagonist was tested in human macrophages and against primary R5 HIV-1 strains, exhibiting cross-clade low picomolar IC50 activity. Moreover, its successful combination with several HIV-1 inhibitors provided the ground for conceiving therapeutic and preventative anti-HIV-1 cocktails. Beyond HIV-1 infection, these CCL5 derivatives may now be tested against several inflammation-related pathologies where the CCL5:CCR5 axis plays a relevant role.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Mutagênese / HIV-1 / Quimiocina CCL5 / Fármacos Anti-HIV / Lactobacillus Limite: Humans Idioma: En Revista: Sci Rep Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Itália País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Mutagênese / HIV-1 / Quimiocina CCL5 / Fármacos Anti-HIV / Lactobacillus Limite: Humans Idioma: En Revista: Sci Rep Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Itália País de publicação: Reino Unido