Transitioning therapeutic peptide programmes from research to clinic
Dr Alastair Hay of Almac Group walks through some of the key considerations facing the transition of peptide therapeutic programmes to clinic
Figure 1 - Factors influencing molecular design of peptide therapeutics
Interest in peptide therapeutics has grown enormously over the last 20 years . In many ways , peptides are the ideal molecular class for therapeutics because they tend to have high levels of specificity and low toxicity . On the downside , peptides are easily degraded by proteases and they have poor oral bioavailability . Formulation can also be challenging because peptide therapeutics tend to be injectables . This combination of inherent properties in peptides makes for an interesting journey from research to clinic , capitalising on sophisticated molecular design , but trading off with manufacturability and potential formulation challenges .
Grand designs
Many therapeutic peptide candidates derived from a natural molecule or a library screen are likely to undergo chemical structure modification to enhance their properties before the final lead is chosen . A very wide range of molecular options is available to modify the candidate properties and overcome issues like protease instability and physiological half-life , or to ensure suitable formulation ( Figure 1 ). A consequence of the propertyenhancing molecular variations is that , while it is very easy to design a molecule with preferred features , there may be manufacturing challenges or unintended physicochemical properties . Many design features have significant impacts on the base peptide structure as changes like the inclusion of functionality to enable cell-penetrating properties , the addition of a half-life extension moiety or the introduction of functionality to enable conjugation to a payload are incorporated .
Manufacturability
One of the key by-products of increased complexity in the molecular design of peptide therapeutics is the impact on manufacturability . There has always been an element of decision-making in terms of selecting the appropriate methodology for peptide manufacture .
For example , a short peptide that is required on a tens of kilos scale may be best tackled by a solution-phase route . On the other hand , a mid-length peptide of 30 amino acids that is required on a hundreds of grams scale would be best approached using a solid-phase synthesis route . As more complex peptide leads proceed through pre-clinical studies , manufacturability is an important consideration during the molecule design phase . Manufacturability can be broken down into a number of considerations :
• Yield : Complex structures are likely to have a lower manufacturing yield , affecting manufacturing economics
• Raw material availability : Molecules that have complex structures may use exotic building blocks that might be available at research scale , but do not have the reliable supply required for scale-up
• Applying new chemistry : Trends appear in the type of chemistry employed . For example , cycloaddition reactions between alkyne and azide functionalities
46 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981