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).
Author interview
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 interaction happens in a precise, programmed, and controlled manner, critical for ensuring proper cellular function. Disruption or imbalance in either protein can lead to aberrant protein production and disease, notably cancer.
This molecular-level understanding of disease origin also offers an opportunity for therapy. In this regard, we have designed and developed peptide molecules that specifically interact with eIF4E, preventing its interaction with eIF4G. Through computational modelling, chemical synthesis, and experimental validation, we demonstrated these peptides’ capability to modulate this critical interaction.
“[…] 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 a powerful strategy for targeting protein-protein interactions. Modern medicinal chemistry allows chemical modifications on peptides, improving their drug-like potency. Since eIF4E overexpression and its interaction with eIF4G are linked with cancer, inhibiting this interaction is a validated approach in anticancer therapeutics. Therefore, our reported peptides serve as important lead compounds for cancer-related drug development.
What was the exciting moment (eureka moment) during your research?
The essence of this work lay in the systematic exploration and optimization of peptide derivatives.
One key insight was that incorporating helix-inducing non-natural amino acid (“Aib”) didn’t automatically increase helicity. It had to be inserted strategically within the peptide sequence. Another exciting moment was the validation of our computational predictions—that peptides predisposed to a bound conformation in their free state showed higher affinity (lower KD) for eIF4E. Peptides with ordered conformations and higher helical content turned out to be potent binders, validating our design.
What do you hope to do next?
Despite their potential, peptide-based drugs face major limitations due to poor cellular membrane permeability. Since most protein-protein interactions occur inside the cell, this is a major bottleneck in developing peptide drugs.
I aim to pursue a research program that explores how chemically modified peptides can effectively penetrate cellular membranes. Unravelling this molecular mystery is crucial for realizing the full therapeutic potential of peptides.
Where do you seek scientific inspiration?
I believe curiosity is the soul of science. My motivation comes from a constant desire to learn and discover. If we can make even one important discovery that furthers scientific knowledge and helps society, it’s worth all the effort. Every day is a step towards that goal.
How do you intend to help Indian science improve?
While I don’t claim to have a fixed roadmap, I believe scientific conduct abroad reflects back home. Doing good work anywhere can influence how people perceive Indian science and scientists. It’s about being a representative of your country through quality research and integrity.
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.
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