PEGylating small molecules
Is small-molecule PEGylation technically and commercially feasible? If the benefits of macromolecular PEGylation are well
understood, so too are the challenges. The principal challenges of PEGylating macromolecules are identifying the specific
sites of PEGylation and characterizing the final product created when a 5000–40,000-dalton PEG molecule is attached to a 5000–50,000-dalton
drug molecule. Properly designed, a PEGylated drug exhibits increased half life, greater bioavailability, and reduced clearance,
which more than compensate for its reduced target binding. But what challenges are involved in PEGylating a 500-dalton drug
that must have oral bioavailability? The feasibility of this process seems dubious, but it has proven possible.
Choice of molecule.
The small-molecule universe encompasses a vast number of compounds, some of which are approved (and available by prescription
or over the counter), some of which are in clinical trials, and some of which are in the early stages of discovery research.
Many of these drugs possess poor physicochemical properties and demonstrate suboptimal efficacy or pharmacokinetics, making
them potential candidates for PEGylation. No inherent technical constraints apparently exist (for experienced medicinal and
PEGylation chemists) that limit the molecules that can be PEGylated. The first challenge is to choose compounds whose performance,
clinical efficacy, and market potential are substantially limited by their oral bioavailability, solubility, half-life, or
immediate clearance by first-pass metabolism. PEGylation can be used to exclude drugs from certain physiological compartments,
such as the central nervous system (CNS), by impeding passage across the blood–brain barrier. This modification can reduce
a drug's side effects.
Next, the chemistry and structure-activity relationships (SAR) of the molecule must be considered and understood. Though it
is hypothetically possible to PEGylate all small-molecule drugs, small molecules lack macromolecules' multiplicity of attachment
sites. The availability of these nucleophilic sites and the feasibility of engineering them in must be considered. A key component
to this decision is whether these sites, whether natural or engineered, will impede target binding to the point of negating
the pharmacokinetic benefits of PEGylation. This decision requires not just an extensive knowledge of a candidate drug's SAR,
but also an experience-based understanding of the effect of PEGylation: a combination of the art and science that frequently
perfects the drug.
Multiple PEG platforms.
Although PEG technology is conceptually simple, its execution is not. Multiple platforms are required to ensure the widest
availability of small-molecule choices and the greatest variety of drug enhancements. Nektar Therapeutics (San Carlos, CA)
employs two basic platforms based on the molecular weight of its PEGs. Both platforms confer the pharmacokinetic benefits
of PEG but are employed based on a drug's specific characteristics such as its route of administration. The large molecular-weight
platform involves PEGs whose molecular weights range from 1000 to more than 60,000 daltons. This platform involves a prodrug
approach with the goal of increasing the circulating half life and extended exposure of drugs that are administered parenterally.
The small molecular-weight platform involves PEGs that have a much lower molecular weight. This platform is exceptionally
useful in creating or increasing oral bioavailability and decreasing penetration of specific barriers.
In addition to molecular weight, other important parameters must be considered when choosing PEGs. These include PEGs' architecture,
which can be linear, branched, or forked (branched PEGs impart a greater degree of steric hindrance to enzymatic degradation)
and the number of binding sites required (which can be manipulated through the choice of architecture and methoxy caps). The
selection and design of the optimum PEG from the permutations available is ultimately dictated by the profile of the parent
drug and the enhancements required to optimize it.
Table III: Advances in PEGylation technology.
Table III summarizes current advances in PEG technology. Using these advances, small molecules can be successfully PEGylated,
but challenges exist. These challenges are as follows:
- Proximity of the PEG chain to the target binding site can reduce drug activity significantly
- The scarcity of potential PEG conjugation sites on a small molecule can require sites to be engineered in
- The optimum conjugation position to choose is not always immediately obvious without substantial expertise in medicinal chemistry,
PEGylation, and SAR
- Many active small molecules require organic environments, in contrast to aqueous-based proteins
- A fine balance must be struck between enhancing a drug's properties and increasing its molecular weight past the point of
Several noteworthy examples of PEGylated small molecules show that these challenges can be overcome.