Chiranjeev Sharma: Targeting Factor XIa with the Synthetic Inhibitor SB-01
Chiranjeev Sharma, Postdoctoral Fellow at Virginia Commonwealth University, shared Umesh Desai’s post on LinkedIn:
“Excited to share that our work is now published in Blood Advances!
This has been a massive collaborative effort involving scientists with diverse expertise.
I am especially grateful to have contributed to the biochemical and biophysical characterization of SB-01 and to the investigation of its allosteric mechanism of action, as we worked together to advance this promising compound as a potential novel antithrombotic strategy.
Beyond its therapeutic potential, this work also highlights the exciting possibilities of sulfated glycosaminoglycan mimetics as drug-like molecules for therapeutic development.
Congratulations to the entire team!”
Umesh Desai, Alfred and Frances Burger Professor of Medicinal Chemistry at Virginia Commonwealth University, shared a post on LinkedIn about a recent article he and his colleagues co-authored, published in Blood Advances, adding:
“Highly promising small molecule, allosteric inhibitor of thrombosis, especially cancer-associated venous thrombosis.
Our comprehensive work on designing, developing and derisking a small molecule as a highly potent (6 mg/kg) inhibitor SB-01 of thrombosis in mice by targeting factor XIa has just been published in Blood Advances.
In this work, we describe the 8-step synthesis, allosteric mechanism of action, identification of site of binding, in vitro, ex vivo and in vivo antithrombotic activity, toxicological safety (bleeding, body weigth/mobility, metabolic (CYPs), cardiac (hERG), hematological (blood count), etc), and ex vivo reversibility in one paper!
Have to thank my team of 15 dedicated scientists for their patience and preseverance for this massive piece of work.
Through this work, we also make a more fundamental and crucial point that non-saccharide synthetic mimetics of glycosaminoglycans (GAGs), that we refer to as NSGMs, can indeed yield drug-like molecules with excellent potency, selectivity and safety window, despite the commonly held belief by medicinal chemists that drugs have to be small and hydrophobic.
Once again, thanks to my major collaborators including Dr. Dhanesha (Louisiana State University – Shreveport), Dr. Erika Martin (VCU School of Medicine), Dr. Masahiro Sakagami (VCU School of Pharmacy), Dr. Bhaumik Patel (Richmond Veterans Affairs Medical Center), Dr. Sridhar Iyer (India) and their lab/group students/scientists.
It would not be possible to develop such a molecule without this team!”
Title: A Synthetic, Small Molecule, Allosteric Inhibitor of Human Factor XIa for Thrombosis
Authors: Chiranjeev Sharma, Rama Gunta, Sridhar R Iyer, Rawan M Fayyad, Elsamani Abdelfadiel, Andrew K Hadsdy, Erika Martin, Priyanka Mishra, Bharath Kumar Villuri, Nilesh Pandey, Daniel K Afosah, Nehru Viji Sankaranarayanan, Bhaumik B Patel, Masahiro Sakagami, Nirav Dhanesha, Umesh R Desai
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