Rational Engineering of a Sub-Picomolar HIV-1 Blocker
Secchi M. Vangelista L.
November 2022MDPI
Viruses
2022#14Issue 11
With the aim of rationally devising a refined and potent HIV-1 blocker, the cDNA of CCL5 5p12 5m, an extremely potent CCR5 antagonist, was fused to that of C37, a gp41-targeted fusion inhibitor. The resulting CCL5 5p12 5m-C37 fusion protein was expressed in E. coli and proved to be capable of inhibiting R5 HIV-1 strains with low to sub-picomolar IC50, maintaining its antagonism toward CCR5. In addition, CCL5 5p12 5m-C37 inhibits R5/X4 and X4 HIV-1 strains in the picomolar concentration range. The combination of CCL5 5p12 5m-C37 with tenofovir (TDF) exhibited a synergic effect, promoting this antiviral cocktail. Interestingly, a CCR5-targeted combination of maraviroc (MVC) with CCL5 5p12 5m-C37 led to a synergic effect that could be explained by an extensive engagement of different CCR5 conformational populations. Within the mechanism of HIV-1 entry, the CCL5 5p12 5m-C37 chimera may fit as a powerful blocker in several instances. In its possible consideration for systemic therapy or pre-exposure prophylaxis, this protein design represents an interesting lead in the combat of HIV-1 infection.
CCL5 , CCR5 , drug combination , entry inhibitor , HIV-1 , protein engineering
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Protein Engineering and Therapeutics Group, Department of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, 20132, Italy
DNA Enzymology and Molecular Virology Unit, Institute of Molecular Genetics, National Research Council, Pavia, 27100, Italy
Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Nur-Sultan, 010000, Kazakhstan
Protein Engineering and Therapeutics Group
DNA Enzymology and Molecular Virology Unit
Department of Biomedical Sciences
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