Key result
Targeting nNOS-mediated protein-protein interactions with small molecule inhibitors provides a promising therapeutic strategy for neurological and neuropsychiatric disorders without the severe side effects of direct nNOS inhibition.
Why the study?
Direct nNOS inhibition benefits various neurological and neuropsychiatric disorders but causes severe side effects, making targeting nNOS-mediated protein-protein interactions a potentially preferable therapeutic strategy.
Targeting nNOS-mediated protein-protein interactions represents a promising strategy for treating neurological and neuropsychiatric disorders while avoiding the side effects of direct nNOS inhibition.
May support safer nNOS-targeted therapies in neurological disorders; leaves open prospective clinical validation.
Neurological and neuropsychiatric disorders are one of the leading causes of disability worldwide and affect the health of billions of people. Nitric oxide (NO), a free gas with multitudinous bioactivities, is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase (nNOS) in the brain. Inhibiting nNOS benefits a variety of neurological and neuropsychiatric disorders, including stroke, depression and anxiety disorders, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, chronic pain, and drug addiction. Due to critical roles of nNOS in learning and memory and synaptic plasticity, direct inhibition of nNOS may cause severe side effects. Importantly, interactions of several proteins, including post-synaptic density 95 (PSD-95), carboxy-terminal PDZ ligand of nNOS (CAPON) and serotonin transporter (SERT), with the PSD/Disc-large/ZO-1 homologous (PDZ) domain of nNOS have been demonstrated to influence the subcellular distribution and activity of the enzyme in the brain. Therefore, it will be a preferable means to interfere with nNOS-mediated protein-protein interactions (PPIs), which do not lead to undesirable effects. Herein, we summarize the current literatures on nNOS-mediated PPIs involved in neurological and neuropsychiatric disorders, and the discovery of drugs targeting the PPIs, which is expected to provide potential targets for developing novel drugs and new strategy for the treatment of neurological and neuropsychiatric disorders.
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Yuanyuan Gu (2021) conducted a review in Neurological and neuropsychiatric disorders. nNOS-mediated protein-protein interaction inhibitors was evaluated. Targeting nNOS-mediated protein-protein interactions with small molecule inhibitors provides a promising therapeutic strategy for neurological and neuropsychiatric disorders without the severe side effects of direct nNOS inhibition.
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