Developing Sphingosine-1-Phosphate (Spns2) Inhibitors for the Treatment of Multiple Sclerosis

Autoimmune diseases are caused when a person's immune system attacks its own healthy cells. In a person with multiple sclerosis, their immune system becomes sensitized to the myelin sheath that covers their neurons in the central nervous system. This results in the degradation of the myelin sheath and irreversible degradation of the nerve cell axons. This damage leads to the development of several neurological impairments, such as pain, fatigue, mobility problems, and numbness. While there is no cure for multiple sclerosis, disease-modifying therapies are typically taken by patients to suppress their immune system and slow disease progression. Sphingsoine-1-phosphate (S1P) is a lipid that is important for the trafficking of lymphocytes into a person's central nervous system. This trafficking is largely due to the natural gradient of S1P which is high levels in blood but low in tissues. Lymphocytes will follow this gradient from areas of low S1P concentration (lymphatic tissue) to areas with higher S1P concentrations. Modulation of S1P levels is the mechanism of action for several FDA approved drugs as they target primarily S1P1 receptors to achieve lower levels of circulating lymphocytes. However, targeting this receptor also results in cardiovascular side effects such as first-dose bradycardia. The transporter for S1P, spinster homolog 2 (Spns2), which is upstream of the S1P receptors, is another viable target that our lab has recently been targeting. Spns2 inhibition decreases extracellular S1P levels and result in reduced lymphocytes in mice models. In this dissertation, several inhibitors were developed and assessed for their in vitro and in vivo ability to inhibit Spns2.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2024

Author dc:creator

• Shrader, Christopher Wayne

Chair dc:contributor.committeechair

• Santos, Webster

Committee members dc:contributor.committeemember

• Lowell, Andrew Nesemann
• Mevers, Emily
• Matson, John

• sphingosine-1-phosphate
• s1p
• spns2
• structure-activity relationship study
• spinster homolog 2
• multiple sclerosis

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

vt_gsexam:39500

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/118217