About DAC™

The Drug Affinity Complex (DAC™) technology developed by ConjuChem addresses the longstanding challenge of protecting peptides from peptidase degradation as well as preventing rapid kidney excretion in order to make development of peptide drugs practicable. Our DAC™ technology is based on two features:

  • A synthetic modification of a well characterized peptide moiety can yield a modified peptide analogue containing a reactive chemical group but still retaining most of its original biologic activity; the modified peptide is called a drug affinity complex (DAC™)
  • The attachment of the DAC™ through reaction of the active moiety with the free thiol of cysteine-34 of albumin

The conjugation of a DAC™ to albumin can occur in two ways: in vivo to circulating albumin following parenteral administration, or ex vivo to recombinant or purified albumin, which is then administered parenterally as a preformed conjugate. The covalent attachment of a DAC™ to albumin is permanent so the peptide does not need to be released from its albumin carrier in order to perform its biologic function. The plasma half-life of albumin varies within species: 40 to 48 hours in rats, approximately 60 hours in dogs, and around 15 days in humans.

There are three parts of each DAC™ construct: 

  • The drug component (the portion responsible for biologic activity)
  • A linker attached to the drug component
  • A reactive chemistry group at the opposite end of the linker, usually a soft electrophile selective for thiols; a maleimide is the most useful embodiment

Natural peptides usually degrade rapidly and are quickly cleared from circulation. Covalent attachment to albumin can block both cleavage by peptidases and various mechanisms of clearance of a wide variety of peptides independent of structure, activity, and therapeutic category. In addition, conjugation of the drug to albumin allows for a wide distribution of DAC™ compounds throughout the body—with the exception of the brain because the DAC™ usually does not cross the blood-brain barrier.

The reaction of the DAC™ in vivo is highly selective for serum albumin over other protein alternatives. This is due to the presence of far higher concentrations of albumin in plasma and interstitial fluids, and because it contains a more reactive thiol group (pK ~5.0) than other molecules, such as cysteine (pK ~8.5) and gluthathione (pK ~8.9) found in plasma and lymph. Also, in physiologic state, the thiol of albumin’s cysteine-34 is in its most reactive state (S-anion) towards electrophiles such as maleimide.