Personalized Treatment for Infantile Ascending Hereditary Spastic Paralysis Based on In Silico Strategies.
Matteo Rossi SebastianoGiuseppe ErmondiKai SatoAsako OtomoShinji HadanoGiulia CaronPublished in: Molecules (Basel, Switzerland) (2022)
Infantile onset hereditary spastic paralysis (IAHSP) is a rare neurological disease diagnosed in less than 50 children worldwide. It is transmitted with a recessive pattern and originates from mutations of the ALS2 gene, encoding for the protein alsin and involved in differentiation and maintenance of the upper motoneuron. The exact pathogenic mechanisms of IAHSP and other neurodevelopmental diseases are still largely unknown. However, previous studies revealed that, in the cytosolic compartment, alsin is present as an active tetramer, first assembled from dimer pairs. The C-terminal VPS9 domain is a key interaction site for alsin dimerization. Here, we present an innovative drug discovery strategy, which identified a drug candidate to potentially treat a patient harboring two ALS2 mutations: one truncation at lysine 1457 (not considered) and the substitution of arginine 1611 with a tryptophan (R1611W) in the C-terminus VPS9. With a protein modeling approach, we obtained a R1611W mutant model and characterized the impact of the mutation on the stability and flexibility of VPS9. Furthermore, we showed how arginine 1611 is essential for alsin's homo-dimerization and how, when mutated to tryptophan, it leads to an abnormal dimerization pattern, disrupting the formation of active tetramers. Finally, we performed a virtual screening, individuating an already therapy-approved compound (MK4) able to mask the mutant residue and re-establishing the alsin tetramers in HeLa cells. MK4 has now been approved for compassionate use.
Keyphrases
- amino acid
- drug discovery
- cell cycle arrest
- nitric oxide
- cerebral palsy
- wild type
- induced apoptosis
- amyotrophic lateral sclerosis
- protein protein
- botulinum toxin
- young adults
- drug administration
- upper limb
- stem cells
- case report
- binding protein
- coronary artery
- oxidative stress
- copy number
- emergency department
- cell death
- pulmonary artery
- genome wide
- combination therapy
- density functional theory
- case control
- pulmonary hypertension
- endoplasmic reticulum stress
- molecular dynamics simulations
- cell therapy
- small molecule
- molecular dynamics
- pulmonary arterial hypertension
- positive airway pressure
- congenital heart disease
- muscular dystrophy