The Company’s Module X technology is a proprietary platform which can allow Allostera in less than 90 days to develop Allosteramers™ that can serve as lead drug candidates. The resulting candidates are generally short peptides, made from all D-amino acids, which are potent (IC50 <5nM), specific, active in both in cellular and animal models, stable in the gastrointestinal tract, and whose manufacturing is well known (generally, solid-phase peptide synthesis).

The Module X Process

Allosteramers™ are sometimes inherently orally bioavailable and the resulting active peptides can be screened for oral activity. Allostera’s patent-pending process used for Module X involves the following: (i) determining the three dimensional structure of the target receptor, (ii) finding all external, non-intracellular, flexible loops (ie. that are not internal in structure), and (iii) reproducing the exact sequence from all such loops for use as short peptides (both L and D versions). These peptides are tested for their activities and oral bioavailability. In completing the process against half a dozen different targets, we have consistently had similar results: out of 10 to 20 peptides synthesized against different loops on any given target, generally 30% to 50% have acceptable activity with almost always one or two having potency in the nanomolar range on the first screen.

The Proposed Mechanism (view animation)

As most receptors are known to be in equilibrium between two or more states (e.g., a signaling state and a non-signaling state), it is believed that the external loops of receptors are constantly shifting as the molecule refolds itself into various configurations. Thus, in the modern view of ligand binding, a natural ligand doesn’t change the conformation of a receptor, but more accurately, simply stabilizes the receptor in its signaling state.

The hypothesis behind the activity of an antagonist Allosteramer™ is that it basically does a similar but opposite thing: it stabilizes the receptor in a non-signaling state. It does this by folding itself into the structure of the receptor at the same point as the natural loop on which it is modeled, but at a time when the natural loop is no longer binding, for example, when the receptor is in process of shifting from one state into another. Thus, it is believed that Allosteramers™ have the capability to shift the equilibrium of the receptor towards one state or the other. If the equilibrium is shifted to a non-signaling state, for example by the Allosteramer™ making it more difficult for the receptor to go back into a signaling state, then the Allosteramer™ will be an antagonist or partial antagonist (a "negative allosteric modulator"). If the equilibrium is shifted to a signaling state, then the Allosteramer™ will be a "positive allosteric modulator"; i.e. it will make the signal stronger in the presence of the ligand. Our screening detects positive allosteric modulators in approximately 1 out of 10 active Allosteramers™.

Benefits of Allosteric Modulation

Because the Allosteramer™ binds to an area of the receptor engineered to be different from the binding site of the natural ligand (i.e. by definition an “allosteric” site), it often does not interfere with the binding of the natural ligand, but only interferes with the signal. This results in an inhibitor which is “non-competitive” with the natural ligand (or “allosteric”). The resulting agent will block the signal even in the presence of high levels of natural ligand. This factor may be a key advantage in the efficacy of Allosteramers™, especially against receptors that respond to high local levels of natural ligand or cytokines in the body (such as the IL-1 receptor). Allosteric modulation also has the advantage of being able to affect some signals and not others. This is termed "pharmacological selectivity."

Success of Module X

We have used the Module X technology to find Allosteramers™ against seven different targets with remarkably consistent results. We also plan to continue to screen for Allosteramers™ with inherent oral activity. Allostera’s Module X platform has been used to develop the Company’s current pipeline of products and we believe the platform will allow the Company to continue to develop a rich pipeline of new drug candidates against validated or “hot” targets in the future in order to capture composition of matter around these targets.