MAGICally drugging the Undruggable

Many human diseases are caused by aberrations in one or more protein molecules. Proteins are products of genes. Often genetic changes result in creating defective and unhealthy protein variants. In humans, over 4000 gene products are linked to certain disorders and traits. However, many of these disease-causing proteins are unreachable therapeutically due to lack of 3D structural characteristics for binding to a small molecule drug. 

Undruggable drug targets refer to clinically meaningful protein targets which are pharmacologically 'difficult to drug' via traditional approaches.

    In the recent years, researchers, policy makers and commercial entities have all become increasingly interested in the adoption of personalized medicine in health care. Rightly so, because the estimated total market size for personalized medicine worldwide is valued at around staggering 2.8 trillion U.S dollars (United States; Statista estimates; Grand View Research; as of June 2016). A biggest challenge to precision or personalized medicine is the lack of drug discovery approach which allows us to generate therapeutics that can distinguish target proteins based on single amino acid difference. Almost all of the human diseases are either caused by or linked to non-synonymous single nucleotide variations (nsSNVs) which result in amino acid change in the proteins thereby altering their biological function. In fact many of our morphological traits are manifested due to single amino acid differences in certain protein molecules. A genetic variant or allelic variant-specific biologic therapeutics is an extremely fascinating idea that has the potential to solve the “Undruggability” challenge. Such bioactive molecules are necessary for not only figuring out the mechanistic basis of genotype-to-phenotype associations but also to advance the field of precision medicine. Until now, an allelic protein variant-specific knock-down approach which does not involve genome editing has been lacking.

    In a story published in ChemBioChem, I describe an accidental finding that is turned into a problem-solving method. In one sentence, my work reveals that phospholipid conjugated point-mutation specific antibodies (MAL-mAbs) are transformed into biologically active agents that exhibit membrane anchorage-induced (MAGIC) knock-down of allelic protein variants at the protein and mRNA levels. MAL-mAbs are biologically inactive in cells where the epitope for binding is unavailable, rendering it free of off-target effects. MAGICally drugging the Undruggable is the new kid on the block for protein knockdown strategies catering to the needs of Individualized (Personalized) Medicine.

Using this approach, for the first time it is now possible to selectively target polymorphic protein variants or disease-causing mutations in an allele-specific manner while leaving the healthy cells expressing wild type protein unaffected. 

  

This also suggests that species-specific protein variant can also be targeted for knockdown, paving the way for tackling parasitic pathogens or intracellular microbes. The emergence of this approach as a new technology platform with the potential to alter the field of drug discovery is on the horizon.

If you are a drug discovery StartUP or early stage biologic drug discovery company focused on developing biologic therapeutics against human genetic disorders, please don’t hesitate to contact us. 

We offer you a viable reduction-to-practice (RTP) solution for your challenging targets using minimum resources within a short period of titme.