Bio Patrika interviews Dr. Lama on his thoughts about “targeting intrinsically disordered peptides in oncology”

Dr. Dilraj Lama’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Dr. Lama is currently working as a Senior Researcher in Prof. David Lane’s Group at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Sweden. Dr. Lama published a paper titled “Conformational ordering of intrinsically disordered peptides for targeting translation initiation” as the senior author in Biochimica et Biophysica Acta (BBA) – General Subjects journal (2020).

How would you explain your paper’s key results to the non-scientific community?

Communication between protein molecules is a fundamental activity behind the execution and regulation of almost all cellular processes. The cell contains a gamut of protein molecules. Each of them interacts with one or a host of other partners, thereby forming a massive network of protein-protein interactions often called the “protein interactome”. The interaction between two proteins called “eIF4G” and “eIF4E” is one such important communication in the interactome that initiates a molecular pathway which culminates in the synthesis of all proteins in the cell. This protein-protein interaction happens in a precise, programmed and controlled manner, which is critical for ensuring the required protein levels in the cell for its proper functioning. A disbalance in either of the protein components will cause an aberration in the pathway that can lead to unregulated protein production and disease conditions, prime among which is cancer. This molecular-level understanding of the cause of disease also provides an opportunity for developing medicine and treatment. In this regard, we have designed and developed peptide molecules that can specifically interact with eIF4E. This was possible through a collaborative effort that involved computational modelling of the peptides, followed by their chemical synthesis and finally experiments to validate their capability to engage the target protein eIF4E, which should prevent its interaction with eIF4G (Figure 1). The study collectively highlights the successful development of peptide-based compounds and modulation of biologically important interaction for potential biomedical applications.

Figure 1. Schematic representation of the research workflow.

“[…] study collectively highlights the successful development of peptide-based compounds and modulation of biologically important interaction for potential biomedical applications.”

What are the possible consequences of these findings for your research area?

Peptide-based drug development is emerging as one of the most exciting and effective approaches to target protein-protein interactions for therapeutic interventions. One of the primary reasons for this development is the currently available technology in medicinal chemistry, making it extremely feasible to make chemical modifications on peptides that significantly improve their potency as drug candidates. The progression of numerous types of cancer is directly or indirectly associated with the overexpression of eIF4E and consequently, the aberrant activity of eIF4G: eIF4E interaction. Hence, it is a well validated system for anti-cancer therapeutics and numerous approaches are being undertaken to specifically inhibit this interaction. It is a vibrant and active area of research. Therefore, the peptide molecules reported in our research are important lead compounds in the continuous effort to develop molecules for potential cancer-based drug development.

What was the exciting moment (eureka moment) during your research?

The essence of the current work lay in the systematic exploration and optimization protocol that had to be undertaken to engineer the peptide derivatives. One of the interesting observations during the research work was that introducing helix-inducing non-natural amino acid popularly called “Aib” did not necessarily improve the helical content of the peptides (Figure 2). Instead, we found that they have to be inserted strategically along the peptide sequence to obtain the desired effect. Besides, the other exciting moment was the validation of our rational design of the peptides. Based on computational modelling, we predicted that free peptides that have pre-disposed bound state conformation in free states should have a higher affinity (lower KD value) for the eIF4E protein target (Figure 2). Indeed, the designed peptide derivatives with ordered conformation and higher helical structures were potent binders. Such validation of predictions is always a moment of eureka for a computational biologist.

  Figure 2. The figure illustrates the different peptide derivatives with their measured binding affinity (KD values) for eIF4E and based on which they are classified into separate binder class. The peptides are shown in cartoon, eIF4E protein in surface and non-natural Aib amino acid in stick representations. A modelled complex of the best binder peptide with eIF4E is also depicted.

What do you hope to do next?

The complete therapeutic capability of chemically modified peptide-based drug molecules is far from being even remotely attained despite its immense potential to target and inhibit protein-protein interactions. The leading cause for this limitation is their poor inherent property to cross the membranes that protect cells. The bulk of the human protein interactome are present inside the cell, so it is a major bottleneck in the progress and growth of these compounds into medicines. Thus, unravelling this mystery is currently a high-priority research goal. I aim to embark on a research program to address this challenging yet exciting subject matter to uncover the finer molecular fingerprints required for chemically modified peptides permeation into the intracellular environment.

Where do you seek scientific inspiration?

I believe curiosity is at the core of any scientific endeavour. My inspiration is subconsciously fuelled by this constant desire to learn and discover. As researchers, we will be fortunate to discover one important finding during our carrier that will further the knowledge and hopefully have some tangible impact. And so, every day is just a constant drive in that direction.

How do you intend to help Indian science improve?

I cannot claim to have any specific course of action that will directly impact the nature of scientific discourse in India right now. However, I strongly believe that our scientific conduct anywhere in the world can go a long way in shaping peoples’ perspective towards the scientific culture back home. So at this point, it is all a matter of doing good work, which is a personal endeavour, but one which can also have a constructive influence in general as we are all in a way representative members of our country.

Reference

Brown CJ*, Verma CS, Lane DP, Lama D*. Conformational ordering of intrinsically disordered peptides for targeting translation initiation. Biochim Biophys Acta Gen Subj. 2021 Jan;1865(1):129775.

Email: dilraj.lama@ki.se

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