bioTIMERS: Tunable IntraMolecular Enzyme Regulation System

Spanning from heart attacks and strokes to peripheral artery disease, cardiovascular diseases constitute the leading cause of mortality, accounting for 32% of all deaths worldwide in 2019. A key medical intervention in these emergencies involves managing and preventing blood clots that have triggered the acute injury with medicines that function as blood thinners. Although interventional procedures to remove or dissolve blockages play an important role, most existing treatment strategies impact the entire body, creating hazards where medications that have successfully dissolved clots in one area can nevertheless trigger bleeding elsewhere. For patients simultaneously experiencing both clotting and bleeding (due to conditions such as COVID-19, surgical complications, traumatic injury, etc.), physicians must walk a tightrope, facing agonizing choices as managing clotting increases the risk of bleeding. Thus, in this complex clinical setting, methods for additional fine tuning are much needed to deal with the challenge of interlocking clotting and bleeding. Here we propose a new concept that aims for much higher precision in where and when a medicine shows a therapeutic effect. To achieve this, we have envisioned time-regulated tools that influence the complex processes leading to clot formation and dissolution. To investigate this new concept, we will program specific key players involved in the clotting process using chemical strategies that allow us to control when the biological machinery is ON/OFF and test them in blood samples. This programmed mechanism is controlled by engineered chemical reactions that proceed safely and efficiently under physiological conditions. I have recently discovered a new mechanism that allows us to choreograph such chemical reactions and accurately control the order of events in a biological environment. Initially, we will introduce our control mechanism in model systems, test their functionality, and study their stability in blood samples. We will then develop a library of building blocks and assemble them with the key therapeutic enzymes. Subsequently, we will investigate the function of our new control circuit and explore its ability to function as a timer, controlling the therapeutic duration of clot formation or dissolution. Overall, we aim to gain a deeper understanding of a potential new approach for managing clotting and bleeding. If successful, this would be a first step towards hematologic medicines that would allow clinicians to administer therapies with a new degree of precision control for when and where they are activeat a particular site, in a particular organ, or in a particular blood vesselachieving positive treatment outcomes with a highly reduced risk of side effects elsewhere in the body.