1 research outputs found
Multivalent Antiviral XTEN–Peptide Conjugates with Long in Vivo Half-Life and Enhanced Solubility
XTENs are unstructured, nonrepetitive
protein polymers designed
to prolong the in vivo half-life of pharmaceuticals by introducing
a bulking effect similar to that of polyÂ(ethylene glycol). While XTEN
can be expressed as a recombinant fusion protein with bioactive proteins
and peptides, therapeutic molecules of interest can also be chemically
conjugated to XTEN. Such an approach permits precise control over
the positioning, spacing, and valency of bioactive moieties along
the length of XTEN. We have demonstrated the attachment of T-20, an
anti-retroviral peptide indicated for the treatment of HIV-1 patients
with multidrug resistance, to XTEN. By reacting maleimide-functionalized
T-20 with cysteine-containing XTENs and varying the number and positioning
of cysteines in the XTENs, a library of different peptide–polymer
combinations were produced. The T-20-XTEN conjugates were tested using
an in vitro antiviral assay and were found to be effective in inhibiting
HIV-1 entry and preventing cell death, with the copy number and spacing
of the T-20 peptides influencing antiviral activity. The peptide–XTEN
conjugates were also discovered to have enhanced solubilities in comparison
with the native T-20 peptide. The pharmacokinetic profile of the most
active T-20-XTEN conjugate was measured in rats, and it was found
to exhibit an elimination half-life of 55.7 ± 17.7 h, almost
20 times longer than the reported half-life for T-20 dosed in rats.
As the conjugation of T-20 to XTEN greatly improved the in vivo half-life
and solubility of the peptide, the XTEN platform has been demonstrated
to be a versatile tool for improving the properties of drugs and enabling
the development of a class of next-generation therapeutics