PERFORMANCE-ENHANCED SYNTHETIC NONAKINE IS A HIGHLY POTENT INHIBITOR OF HIV-1 INFECTION
The discovery that N-terminal modification of the human chemokine RANTES inhibits NSI/R5 HIV-1 entry through downregulation of the HIV-1 co-receptor CCR5 has open new doors for the prevention and treatment of HIV-1 disease. Using Gryphon’s chemical protein synthesis (CPS) and precision length polymer technology, we have synthesized several RANTES analogs (Nonakine). These molecules feature unnatural amino acids and defined length polymers to, respectively, improve their efficacy and pharmacokinetics profile as compared to wild type RANTES.
Nonakines inhibit infection of PBMC in vitro by (R5) HIV-1 primary clinical isolates from subtypes A, B, C, D, E, F, G and O with IC50 in the low to sub nM range. This antiviral activity is independent of the timing of drug addition to cell cultures. Nonakine’s antiviral efficacy synergies with that of approved reverse transcriptase inhibitors and protease inhibitors anti-HIV drugs. The in vivo antiviral efficacy of Nonakines against (R5) clinical isolates (subtype B) is being evaluated in the Hu-PBL-SCID mouse model. The attachment of precision length polymer significantly prolongs the elimination half-life of the molecules. For one analog, a serum concentration of Nonakine corresponding to 100 x the IC50 against the primary clinical isolate 92/US/712 was detectable more than 24 hours following a single IV injection. Finally, the preliminary report from a pilot toxicology study in rodent indicates that Nonakines are safe.
These data suggest that these novel RANTES analogs have great potential as AIDS therapeutics. Results from all efficacy and PK studies will be evaluated shortly and a lead analog selected for clinical development.
X. Paliard1, A.Y. Lee1, N. Fraud1, D. Low1, D. Song1, J. Turpin2, A.H.C. Kung1
1Gryphon Therapeutics, South San Francisco, CA, USA, 2TherImmune Research Corporation, Gaithersburg, MD, USA
Gryphon Therapeutics, South San Francisco, CA, USA