The lord of permeability

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For the sake of understanding, all references to LOTR will be reflected in italic.

Time ago, in the Middle-earth, a diminutive humanoid with hairy feet, changed the rules. Maybe everybody thought of them as farmers, but halfling were capable of greater things. And there was one of them that stood out amongst all others. A hobbit, a shrugged off person never considered as a warrior, challenged and defeated the most powerful, dark and terrifying army.

In the war of drug discovery, Protein-Protein Interactions (PPIs) may be referred as the most fearsome troop. With indestructible weapons, PPIs are able to trigger damaging cascades that eventually provoke fatal events, from uncontrolled cell division to self-body attack. Among PPIs, the intracellular squads are the most arduous to combat. With solid defenses and impassable boundaries, intracellular PPIs remain isolated, being out of the reach from extracellular small drug catapults, which were retained in the first-enemy line.

PPIs are large, flat and flexible surfaces that canonical small molecules cannot cover. As discussed previously, peptides represent a powerful solution to modulate PPIs. But before reaching the target, compounds have to follow a long way, just as the one from Shire to Mordor. In the journey to the target binding (or ring destruction) molecules encounter a collection of molecular and physiological barriers that risk the integrity of the drug entities [1].

Most powerful kingdoms have sent their best soldiers to confront PPIs, failing in many attempts. Small molecules have been ineffective, and peptides have poor pharmacokinetic profile, consequence of their low solubility, little permeability, increased efflux and high metabolism [2].

But this is not a typical battle and so must not be the fighters. In the same way that Frodo was able to change the war rules, peptidomimetics have managed to go beyond the rule of 5 [3], and demonstrate their value as champions. One molecule type to rule them all.


Before starting the journey, think in the opposite and imagine that the peptidomimetic is the Balrog and our body is Gandalf. “You shall not pass”, may we decisively and strongly pronounce. Typical and vulgar peptides may fail in this mission. However, peptidomimetics wear an Elven cloak that allows them to camouflage and overcome all the obstacles that they may encounter.

First, if the route of administration is oral, peptidomimetics face the gastric and intestinal environment. Hordes of digestive enzymes (hydrolases) combat against the intruder molecules. Glycosidases, ester hydrolases and the most fearsome, peptidases, attack over and over. If peptidomimetic molecules have been successful to the orc-hydrolase offensive, they have to travel through the intestinal mucus barrier and avoid being trapped into the hydrophobic network of mucin proteins, a mortal trap similar to the one of Shelob. Afterwards, peptidomimetics continue the voyage through the Kerckring mountains (Kerckring folds) where they encounter the villi enterocyte [1]. Crossing these epithelial cells to be absorbed and reach afterwards the blood stream is another of the challenges until Mordor. Going though these Rauros falls might appear a crusade, but peptidomimetics know how to secretly pass over the enterocyte river without tumbling to the canyon.

Once in the bloodstream peptidomimetics encounter many other enzymes that may reduce their half-life and endanger the in vivo efficacy. However, their non-codified aminoacids and structural modifications provide a shield that prevents them from hydrolysis of proteases, esterases and other enzymes. Later on, molecules ride until they reach the liver; the Helm’s deep for foreign compounds that navigate through the bloodstream. The microsome battalion, led by cytochrome enzymes (the Uruk-hai) slit and slash molecules with no remorse. It is a stiff, strenuous and severe battle that lessens the population of the non-vigorous compounds armies, but again, peptidomimetics emerge victorious.

Returning to the river of blood, compounds paddle and traverse the whole body, looking for the target to destroy it. And they find its location, but, oh surprise! There is one more obstacle. Just when peptidomimetics could almost touch the PPI with the fingertips, the compounds tackle a rampart: the cell membrane, an infinite watched over surface [4]. Anew, the improved permeability properties of peptidomimetics may make them invisible to the plasma membrane, as if they were wearing The ring, providing them invisibility.

It is the end. Peptidomimetic versus PPI, or Frodo versus Sauron. In the last moment, when the forces were declining, and with faltering energy, the little hobbit is preciously placed at the large PPI surface, accomplishing its mission, destroying the ring and preventing the evil uprising. Finally, it is time for the peptidomimetic to abandon the target and be secreted from our bodies, as Frodo left Middle-earth to go to the Undying Lands.

Success and triumph. This has been the story of how an atypical type of molecule has become the key to fight against malignant intracellular PPIs, and how permeability has played a relevant role in the journey. In the end, peptidomimetics were meant to find the ring.


                              Figure 1. Cyclic petidomimetic (yellow) displayed in the protein surface (green) where it binds to with high affinity.




  1. Oral absorption of peptides and nanoparticles across the human intestine: Opportunities, limitations and studies in human tissues (2016); Advanced Drug Delilvery Reviews, 106 , 256-276
  2. Cell permeability beyond the rule of 5 (2016); Advanced Drug Delivery Reviews, 101, 42-61
  3. Oral druggable space beyond the Rule of 5: Insights from drugs and clinical candidates (2014); Chemistry & Biology, 21, 1115-1142
  4. How big is too big for cell permeability? (2017); Journal of Medicinal Chemistry, 60, 1662-1664