Investigation
of the Effect of Peptide p5 Targeting
CDK5-p25 Hyperactivity on Munc18–1 (P67) Regulating Neuronal
Exocytosis Using Molecular Simulations
posted on 2024-07-02, 11:43authored byTejaswi Tammareddy, Walid Keyrouz, Ram D. Sriram, Harish C. Pant, Antonio Cardone, Jeffery B. Klauda
Munc18–1 is an SM (sec1/munc-like) family protein
involved
in vesicle fusion and neuronal exocytosis. Munc18–1 is known
to regulate the exocytosis process by binding with closed- and open-state
conformations of Syntaxin1, a protein belonging to the SNARE family
established to be central to the exocytosis process. Our previous
work studied peptide p5 as a promising drug candidate for CDK5-p25
complex, an Alzheimer’s disease (AD) pathological target. Experimental in vivo and in vitro studies suggest that
Munc18–1 promotes p5 to selectively inhibit the CDK5-p25 complex
without affecting the endogenous CDK5 activity, a characteristic of
remarkable therapeutic implications. In this paper, we identify several
binding modes of p5 with Munc18–1 that could potentially affect
the Munc18–1 binding with SNARE proteins and lead to off-target
effects on neuronal communication using molecular dynamics simulations.
Recent studies indicate that disruption of Munc18–1 function
not only disrupts neurotransmitter release but also results in neurodegeneration,
exhibiting clinical resemblance to other neurodegenerative conditions
such as AD, causing diagnostic and treatment challenges. We characterize
such interactions between p5 and Munc18–1, define the corresponding
pharmacophores, and provide guidance for the in vitro validation of our findings to improve therapeutic efficacy and safety
of p5.