BME PhD Preliminary Exam Announcement for Anushri Umesh

Everyone is invited to attend the public presentation beginning at 3:00 PM.

Title: Rational Design of Multivalent Plasmin Inhibitors for Use in Antifibrinolytic and Thrombolytic Therapy

Date: October 28th,2025

Time: 3:00 PM

Place: ET103, Engineering and Technology Building799 West Michigan Street, Indianapolis, IN 46202 and Zoom - https://purdue-edu.zoom.us/j/95677660906?pwd=X8XYNbiqWDyifHWmu6s9z9rCW9U0q3.1

Thesis Committee:

Dr. Nathan J. Alves (Major Advisor)

Dr. Sherry L. Harbin (Co–advisor)

Dr. Arun K. Ghosh

Dr. Andrew D. Otte

Abstract:

Plasmin, a key component of the fibrinolytic cascade, offers significant potential for overcoming the main limitations of current thrombolytic and anti-fibrinolytic therapies. t-PA, commonly used for acute thrombolysis, has notable drawbacks, owing to a narrow therapeutic index and an increased risk of systemic bleeding, resulting in high mortality rates. Similarly, TXA, the current anti-fibrinolytic agent, is constrained by a short elimination half-life and a therapeutic window of only 3 hours after injury. Plasmin can function as a central player in both thrombolytic and anti-fibrinolytic therapy development. Its unique position in the hemostasis process renders it a safer enzyme for clot dissolution and a therapeutic target for bleeding control. Multivalency, a phenomenon driven by multiple low-affinity binding events that create a high avidity system, has the potential to drive an orthogonal technology for enzyme inhibition. The aim of this project is to experimentally validate the design of multivalent inhibitors for plasmin that can achieve persistent binding. Rational control over linker length, flexibility, and scaffold topology—by conjugating multiple copies of a known monovalent inhibitor of plasmin—will produce multivalent analogues that exhibit functional affinities (avidity) superior to the parent compound. Such an enhancement in avidity is expected to result in improved and specific enzyme inhibition. Consequently, this strategy will be used to develop safe and efficacious therapies for managing dysregulated hemostatic systems by targeting plasmin. Our approach focuses on developing multivalent inhibitors that directly complex with plasmin for targeted in-vivo delivery as clot busters. It also explores anti-fibrinolytic options to treat severe, life-threatening hemorrhagic conditions.