Process development of TRI-999, a fatty-acid-modified HIV fusion inhibitory peptide

TRI-999 is a HIV fusion inhibitory peptide designed to improve upon the efficacy and convenience of Enfuvirtide (ENF, Fuzeon), the first approved HIV entry inhibitor. Derived from a gp41 HR2 region partially overlapping, the ENF sequence, TRI-999 is modified using a fatty acid conjugation strategy through a poly(ethylene glycol) (PEG) linker to maintain potency while achieving the desired PK. Synthetic route comparison, process development, and GMP manufacturing at the kilo scale of TRI-999 are reported.