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On the therapeutic potential of heparan sulfates Mar 17, 2021
In a recent series of papers, Dr. Raghavendra Kikkeri’s group explores the therapeutic potential of heparan sulfate, a linear carbohydrate (polysaccharide) molecule, which is typically found at the cell surface and in the extracellular matrix that holds cells together.
Shown to be important in several cellular functions including in development and healing, heparan sulfate has been under the limelight for use as an anticancer agent. However, the potential remains unexplored because of the structural microheterogeneity and complexity that limits its use.
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| Heparan Sulfate (HS)/ Heparin chemical structure. R/ R1 depicts potential sites of sulfation. Heparan Sulphate is composed of α(1–4)-linked disaccharide repeating units of d-glucosamine and hexuronic acid, which could be either d-glucuronic acid (GlcA) or l-iduronic acid (IdoA). (Image Credit: Dr. Raghavendra Kikkeri) |
To understand the capabilities of heparan sulfate, Dr. Kikkeri’s group created a library of heparan sulfate fragments and their mimetics and studied their anticancer properties in detail. In this set of papers, employing synthetic heparan sulfate fragments, the group takes on a multi-pronged approach to test the applicability of heparan sulfate in the treatment of cancer.
A nanomaterial-based platform to target cancer cells
Dr. Kikkeri’s group developed a nanomaterial-based platform using synthetic heparan sulfate fragments, in the context of targeted therapy for treating cancer. In targeted therapy, cancer cells are prevented from growing and taking over as opposed to chemotherapy where cancer cells as well as normal cells are both affected. In this paper, the group has identified a suitable target on cancer cells corresponding to the heparan sulfate fragments they employed and found that these HS-based nanomaterials can very precisely escape the normal cells and are further sequestered only in the cancer cells, even in the highly complex heterogeneous tumour microenvironment.
Prashant Jain, Chethan D. Shanthamurthy, Preeti Madhukar Chaudhary and Raghavendra Kikkeri (2021). Rational designing of glyco-nanovehicles to target cellular heterogeneity Chemical Science (Advance Article)
Inhibiting the ability of cancer cells to migrate
In this paper, in collaboration with researchers from Tel Aviv University, Israel, Dr. Kikkeri’s group blocked the ability of cancer cells to migrate, a phenomenon responsible for metastasis. The new heparan sulfate fragments prepared by the Dr. Kikkeri’s group could successfully block the chemokine receptor signaling responsible for the cancer cell movement from one location to another. Additionally, in another paper, de novo heparan sulfate fragment was found to inhibit angiogenesis--a fundamental phenomenon in the transition of tumours from a benign state to a malignant one.
Prashant Jain, Chethan D. Shanthamurthy, Shani Leviatan Ben-Arye, Robert J. Woods, Raghavendra Kikkeri and Vered Padler-Karavani (2021). Discovery of rare sulfated N-unsubstituted glucosamine based heparan sulfate analogs selectively activating chemokines. Chemical Science (Advance Article)
Prashant Jain, Chethan D. Shanthamurthy, Shani Leviatan Ben-Arye, Sharon Yehuda, Sharvani S. Nandikol, Hirekodathakallu V Thulasiram, Vered Padler-Karavani and Raghavendra Kikkeri (2021). Synthetic heparan sulfate ligands for vascular endothelial growth factor to modulate angiogenesis. Chemical Communications (Advance Article)
A novel heparan sulfate mimetic
Unnatural substrates have often offered an attractive approach for treating disease. In this paper, Dr. Kikkeri’s group, in collaboration with researchers from Tel Aviv University, Israel and University of Georgia, USA developed a library of heparan sulfate mimetics and identified one that can inhibit chemokines such that cancer cell invasion and metastasis are blocked. IdoA, the heparan sulfate mimetic that the team identified, contains a scaffold made of iduronic acid, a hexapyranose sugar molecule with different sulfation patterns and oligosachharide chain lengths. Due to the diverse roles of chemokines in physiology, selective inhibition of chemokines has the potential to control inflammation and cancer progression. Chemokines employ heparan sulfate as co-receptors; however, most chemokines can bind to more than one heparan sulfate sequence, and the same sequence may interact with more than one chemokine. As a result, finding a specific heparan sulfate structural domain to modulate individual chemokines has been non-trivial for researchers. This study presents IdoA as a promising candidate to modulate chemokine activity in a more specific manner.
Chethan D. Shanthamurthy, Shani Leviatan Ben-Arye, Nanjundaswamy Vijendra Kumar, Sharon Yehuda, Ron Amon, Robert J. Woods, Vered Padler-Karavani, and Raghavendra Kikkeri (2021). Heparan sulfate mimetics differentially affect homologous chemokines and attenuate cancer development. Journal of Medicinal Chemistry
- With inputs from Raghavendra Kikkeri
