HIV therapy with anti-retroviral drugs is limited by the poor exposure of viral reservoirs, such as lymphoid tissue, to these small molecule drugs. We therefore investigated the effect of PEGylation on the anti-retroviral activity and subcutaneous lymphatic pharmacokinetics of the peptide-based fusion inhibitor enfuvirtide in thoracic lymph duct cannulated rats. Both the peptide and the PEG were quantified in plasma and lymph via ELISA. Conjugation to a single 5 kDa linear PEG decreased anti-HIV activity three-fold compared to enfuvirtide. Whilst plasma and lymphatic exposure to peptide mass was moderately increased, the loss of anti-viral activity led to an overall decrease in exposure to enfuvirtide activity. A 20 kDa 4-arm branched PEG conjugated with an average of two enfuvirtide peptides decreased peptide activity by six-fold. Plasma and lymph exposure to enfuvirtide, however, increased significantly such that anti-viral activity was increased two- and six-fold respectively. The results suggest that a multi-enfuvirtide-PEG complex may optimally enhance the anti-retroviral activity of the peptide in plasma and lymph.
CITATION STYLE
Kaminskas, L. M., Williams, C. C., Leong, N. J., Chan, L. J., Butcher, N. J., Feeney, O. M., … Ascher, D. B. (2019). A 30 kDa polyethylene glycol-enfuvirtide complex enhances the exposure of enfuvirtide in lymphatic viral reservoirs in rats. European Journal of Pharmaceutics and Biopharmaceutics, 137, 218–226. https://doi.org/10.1016/j.ejpb.2019.03.008
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