Protein-Protein Interactions: A Key to Precision Medicine

Protein-protein interactions (PPIs) are the foundation of life, controlling everything from cell growth and division to metabolism and signaling.¹ Targeting PPIs for drug discovery has long been a challenge due to their large and relatively featureless surfaces, making it difficult for small molecules to bind with high affinity and selectivity.² In recent years, however, advancements in DNA-encoded library (DEL) technology have enabled the identification of small molecule inhibitors for PPIs, creating new opportunities for the development of precision medicines.³  

DEL technology is a powerful tool for drug discovery. It allows researchers to screen millions of compounds at once, and it’s particularly effective for targeting PPIs. At X-Chem, we’re leading the way in PPI drug discovery with a proprietary DEL screening approach that’s been used to identify small molecule inhibitors for a variety of PPIs, potentially revolutionizing the way diseases are treated. By targeting PPIs, we can develop more effective and targeted therapies for a host of conditions: 

• Cancer — PPIs play a role in cancer development and progression; by targeting PPIs, new cancer therapies can be developed that are more effective and less toxic 
• Heart disease — PPIs are involved in the regulation of cholesterol levels and blood pressure; by targeting PPIs, new heart disease therapies can be developed to help prevent heart attacks and strokes 
• Alzheimer’s disease — PPIs are involved in the formation of amyloid plaques, which are a hallmark of Alzheimer’s disease; by targeting PPIs, new Alzheimer’s disease therapies can be developed and attempt to slow the progression of the disease 

These are just a few examples of the many ways that PPIs can be targeted for drug discovery. As our collective understanding of PPIs continues to grow, we can expect to see even more new and innovative therapies emerge in the years to come. With our massive compound libraries, decades of experience and industry-leading expertise, X-Chem will remain at the forefront of this ongoing evolution. 

DEL Screening: Delivering Results for Precision Medicine 

Recent work on interfering peptides (IPs) and FDA-approved peptide therapies that target PPIs are adding to the industry’s interest in this class. PPI binding patterns have even been the subject of SARS-CoV-2 research. For example, the binding of the virus’s surface spike glycoprotein to angiotensin-converting enzyme-2 (ACE2) in the lungs — the entry point of the viral genome into host cells — was investigated and potential avenues for drug development were outlined.⁴ This study was followed with designed peptides that could potentially be developed as dual target pan-coronavirus inhibitors⁵… and this is just the tip of the iceberg in new PPI drug research. 

Maximizing the ability to discover new drugs in this class takes an advanced, ultra-high-throughput approach, and our revolutionary DEL screening methods deliver on that requirement. For example, through our DELcore service, we’ve helped partners generate small molecule inhibitors even in cases where no known small molecules existed for a target. In one success story, we delivered an inhibitor for a pro-inflammatory cytokine target that was confirmed for both selectivity (via cellular assays) and target engagement (SPR), leading to clinical trials.  

Our DELflex service is an affordable, full-service hit discovery solution that includes access to X-Chem’s advanced libraries and the guidance of our leading experts. With no downstream financial obligations, partners can leverage X-Chem’s expertise to find the best screening solution for their PPI project, accelerating the hit-to-lead development journey.  

These are just a couple of the ways our technological capabilities and expertise are helping to advance new and innovative PPI therapies to clinic, streamlining the path to market. In a constantly evolving field that’s witnessing breakthrough after breakthrough, advanced DEL technology is the secret ingredient that can help optimize the PPI development process and bring novel therapies to patients. 

Looking Forward: The Future of PPI Drug Discovery 

Small molecules have been the backbone of drug discovery for decades, yet their potential is far from exhausted. With our DEL technology, researchers can now target specific biological pathways with unprecedented precision, leading to the development of new and innovative therapies that are more effective, have fewer side effects and have the potential to improve millions of lives. Deep experience, scientific rigor and vast technical capabilities have put us on the frontier of PPI research, and we’re just getting warmed up.  

With an unwavering commitment to delivering results for partners, X-Chem’s proprietary technology and industry-leading expertise have the potential to transform the way drugs are developed. Collaborating with X-Chem offers partners the opportunity to access a wealth of knowledge and resources, enabling the identification of small molecule inhibitors against even the most challenging PPI targets. The possibilities are truly exponential. 

Conclusion: Unlocking the Potential of Small Molecules 

PPIs have long been considered challenging targets for drug discovery, but new structural and functional discoveries in the field, alongside advancements in DNA-encoded library technology, have enabled the identification of small molecule inhibitors, offering new opportunities for the development of precision medicines. X-Chem’s proprietary DEL screening approach has revolutionized the drug discovery process, enabling the identification of small molecule inhibitors against previously “undruggable” targets.  

The hit-to-lead journey can be tough, so it’s important to find the straightest, surest and lowest-risk path available. Identifying small molecule inhibitors for previously “undruggable” targets like PPIs is where X-Chem excels.  

For full-service PPI solutions that include access to advanced libraries and the guidance of industry-leading experts, find your best path forward with X-Chem. 

References 

1. Rao, V.S. et al. Protein-Protein Interaction Detection: Methods and Analysis. Int J Proteomics, 2014; 2014, 147648.
2. Mabonga, L. et al. Protein-protein interaction modulators: advances, successes and remaining challenges. Biophys Rev., 2019, 11(4), 559–581.
3. Kunig, V.B.K. et al. Scanning Protein Surfaces with DNA‐Encoded Libraries. ChemMedChem, 2021, 16(7), 1048–1062.
4. Jafary, F. et al. In silico investigation of critical binding pattern in SARS-CoV-2 spike protein with angiotensin-converting enzyme 2. Sci Rep., 2021, 11, 6927.
5. Arabi-Jeshvaghani, F. et al. Analysis of critical protein–protein interactions of SARS-CoV-2 capping and proofreading molecular machineries towards designing dual target inhibitory peptides. Sci Rep., 2023, 13, 350.

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