Research Summary: Designed protease-stable, membrane active, gramicidin-inspired peptide-based combination therapy induces mitochondrial depolarization, cell cycle arrest, angiogenesis inhibition, oncogenic pathway disruption and potentiates radiosensitization and immunotherapy in radioresistant metastatic kidney cancer.
Author Interview
Argha Mario Mallick received his PhD from Prof. Rituparna Sinha Roy’s lab, Department of Biological Sciences, IISER Kolkata. He worked on engineered stabilized peptide-based combination therapy against breast and kidney cancer.
Linkedin – https://www.linkedin.com/in/argha-mario-mallick-553210283/
Twitter – https://x.com/ArghaMario
Labs – Prof. Rituparna Sinha Roy, IISER Kolkata and Dr. Anand Srivastava, IISc Bangalore
What was the core problem you aimed to solve with this research? Gramicidin has shown promising results against hard-to-treat cancers and cancer stem cells. However, the haemolytic activity of gramicidin has restricted its use as an anti-cancer drug. We aimed to design a gramicidin-inspired, non-haemolytic peptide with anti-cancer activity and suitability for systemic delivery.
How did you go about solving this problem? We designed a short peptide (around half the length of gramicidin) with alternating L and D amino acids. This strategy made our designed peptide protease stable, non-hemolytic still ensuring that it retains the membrane active properties like that of gramicidin. To enhance the anti-cancer efficacy of the designed therapeutics, a mechanistically rational synergistic combination therapy was developed, leading to the inhibition of the key transcription factor HIF-2α, a critical regulator in kidney cancer.
“This is probably the first study which shows bacterial ion-channel gramicidin-inspired peptide potentiates immunotherapy via T cell and phagocytosis activation.” — Prof. Rituparna Sinha Roy
How would you explain your research outcomes (Key findings) to the non-scientific community? Kidney cancer rates have been increasing, with around 400,000 new cases and 175,000 deaths each year worldwide, especially in lower-income countries. Kidney cancer is generally undetected till advanced stages and treatment for kidney cancer often involves medications like sorafenib, sunitinib, and pazopanib. Other treatments, including immunotherapy drugs like bevacizumab and nivolumab, have not been very effective either. These treatments are expensive and can cause serious side effects, such as high blood pressure, nausea, fatigue, digestive problems, and thyroid issues, while offering little improvement in survival rates. To solve these issues, we have investigated a new class of therapeutics which can facilitate proton transport. Gramicidin, an antibiotic produced by bacteria has proven to effective against hard-to-treat cancer cells. But gramicidin cannot be used as a drug as it causes lysis of red blood corpuscles (RBC). We have designed a gramicidin inspired short peptide which is safe to the RBCs, does not induce any abrupt immune response, stable in serum and does not exhibit toxicity to non-cancer cells. Despite being around half the length of gramicidin our designed peptide could disrupt cancer cell membrane and induce toxicity to kidney cancer cells. The anti-cancer of the designed treatment was enhanced by employing a combination therapy which exhibited synergistic therapeutic effects by disrupting a major protein (HIF-2α), responsible for causing kidney cancer. Our designed therapy caused impaired mitochondrial function, reduced blood supply to tumors, blocked signaling pathways responsible for cancer progression thus reducing kidney cancer cell proliferation as evidenced in lab cell culture conditions and live zebrafish embryo model. Moreover, kidney cancer is notoriously infamous for being unresponsive to radiotherapy and has a microenvironment that suppresses body’s own immune system against the cancer cells. Our designed therapy sensitized the kidney cancer cells to radiotherapy and also potentiated immunotherapy by activating T cells (which kills cancer cells) and increasing phagocytosis (engulfing and destroying) of kidney cancer cells by immune cells.
What are the potential implications of your findings for the field and society? We anticipate that our work will stimulate further investigation into the role of ion channels in cancer and facilitate the design of ion channel-mimicking peptide-based anti-cancer agents, capable of enhancing immunotherapy. Ultimately, we hope our findings contribute to the design of cost-effective therapeutic agents that improve median overall survival in metastatic kidney cancer patients.
What was the exciting moment during your research? Confirming our designed peptide to be non-haemolytic, designing a mechanistically inspired combination therapy and finding it to exhibit synergistic drug interaction, radiosensitization of radioresistant kidney cancer and visualizing increased phagocytosis of kidney cancer cells by our designed therapeutics were some of our most exciting moments during this research.
Paper reference. Biomater. Sci., 2025,13, 4681-4705 https://pubs.rsc.org/en/content/articlelanding/2025/bm/d5bm00109a
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