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Robert Nshimiyimana, PhD
Pronouns
He/Him/His
Job Title
Research Fellow
Academic Rank
Research Fellow
Department
Anesthesiology, Perioperative and Pain Medicine
Authors
Robert Nshimiyimana, Nicos A. Petasis, Charles N. Serhan
Principal Investigator
Charles N. Serhan
Research Category: Allergy, Immunology, Inflammation, and Infectious Diseases
Tags
Human phagocytes have key functions in the initiation and resolution of inflammation (PMID: 24899309). Recently, we achieved the first total synthesis of 4(S),5(S)-epoxy-17(S)-hydroxy-6(E),8(E),10(Z),13(Z),15(E),19(Z)-docosahexaenoic acid (PMID: 35481084), the biosynthetic intermediate of anti-inflammatory and pro-resolving mediators Resolvins D3 and D4.
A stereospecific and chiral pool-based synthetic approach was employed, with key features including epoxide transposition under basic conditions to form the oxirane ring, and a late-stage (Z)-selective Wittig olefination to form the core carbon structure. Next, we assessed and provided evidence supporting the role of this highly labile epoxide (T1/2 ≲ 5 sec; aqueous solutions, pH 7.4) in the biosynthesis of Resolvin D3 and Resolvin D4 by human neutrophils and macrophages (PMID: 34911767).
Resolvins D3 and D4 are potent signaling molecules with protective actions, i.e., limit neutrophilic transmigration and enhance macrophage phagocytosis and efferocytosis. Resolvin D3 was also demonstrated to promote inflammatory resolution and functional neurological recovery following murine spinal cord injury (PMID: 32964315). Further, Resolvin D3 production in humans was recently confirmed in the WARRIOR clinical trial in women with cardiovascular disease (PMID: 34728061), and Resolvin D4 was identified in lower levels in human cerebrospinal fluid obtained from Alzheimer’s disease patients, suggesting its potential use as a biomarker (PMID: 35362880).
Human white blood cells such as macrophages and neutrophils in conjunction with chemical signals play vital roles in protecting the body against infection and unrestrained inflammation (PMID: 24899309). We recently made 4(S),5(S)-epoxy-17(S)-hydroxy-6(E),8(E),10(Z),13(Z),15(E),19(Z)-docosahexaenoic acid (PMID: 35481084), an important molecule that was proven to be the natural biological intermediate of Resolvins D3 and D4. These molecules stop inflammation and possess protective properties.
To produce the synthetic target, we started from simple, commercially available building blocks and relied on chemical reactions that allowed us to control and construct the three-dimensional arrangement of atoms. The physical identity of the target molecule as well as its precursors were determined. Having successfully generated this critical and short-lived natural product, we confirmed its essential role in the biological formation of Resolvins D3 and D4 (PMID: 34911767).
Resolvins D3 and D4 act on immune cells and enhance their ability to protect the tissue by absorbing microbes and harmful particles. In addition, Resolvin D3 was recently shown to restore normal brain functions after a spinal cord injury in mice (PMID: 32964315). In lower levels, Resolvins D3 and D4 were recently measured in a clinical trial in women with cardiovascular disease (PMID: 34728061), and from Alzheimer’s patients (PMID: 35362880), respectively.
