Human body utilizes various metals like, cobalt, zinc, copper, manganese, etc. Sometimes, these metal ions move out of their normal cycle and react with DNA, proteins, amyloid, etc. Int he process of binding with these nucleotides and proteins they exert oxidative stress due to their redox reaction. Thus, we experience hepatotoxicity, nephrotoxicity and neurotoxicity.
Zinc plays a neuron-protective role in case of Alzheimer's. Zinc ions compete with the copper ions for metal binding site of ÃŸ-amyloid protein. As a result, copper-amyloid induced formation of hydrogen peroxide and free radical s does not take place. Some genetic and environmental factors trigger excess production of zinc ions. Binding of excess zinc ion to the amyloid forces it to precipitate over a wide range of pH. Excess zinc thus causes neurotoxicity and is one of the major causes of Alzheimer's disease. Thus, we require drugs which can remove zinc ions from the human brain for the treatment of Alzheimer's disease (AD).
The specificity and efficiency of metal chelator drugs is of prime significance to remove the toxic metal ions from the body. For example, inorganic mercury removing drugs contain sulfhydryl group due to the affinity of mercury for sulfhydryl group, DMSP (Dimethyl sulphonio-propionate)and alpha-lipoic acid are such drugs. Alpha- lipoic acid is not efficient as it loosely carries metal ion thus leaving it again inside the body after picking up from the site of action. This increases the complexities of metal detoxification.
It is important to design lead based compounds to reduce the neurotoxicity associated with AD (Alzheimer's disease). Cyclic compounds with hydrophobic groups are disposed outward analogous to transport the antibiotics. These cyclic compounds hold the metal ions better and do not let them go of it easily. The drug designing process must proceed in a sequential fashion. The starting element is the transport antibiotic, Valinomycin, which is a cyclic peptidomimetic compound known for its efficiency to cross the cell membrane. The mode of action for the transport antibiotic involves the carriage of potassium ions across the cell membrane. Curcumin is known to reduce the cognitive defects.
The factors governing the efficient use of cyclic peptidomimetic compounds for metal detoxification are as follows-
i) The the complex interplay of type, size and polarity of backbone.
ii) Electrostatic stabilization of ions.
iii) Conformational re-organization required in the presence of ion.
The main aim is to lower the molecular weight compounds capable of removing Zinc ions from the human brain.
Cuprous ions compete with zinc ions but the carriage of zinc ions lead to a better electrostatic gain. Sodium and potassium ions can only be carried at the periphery due to their large sizes. Lead compound 3 is too large to carry magnesium ions so it has to reorganize itself a lot to be able to carry them off easily. Lead compound 3 is specific for capturing zinc ions.
The series of cyclic peptidomimetic compounds is being studied. Lead compound 3 containing CH2NH backbone in 2,4,2,4 cyclic systems with glycine, alanine, ethyl type substituent is suggested as the optimum choice with moderate balance of low conformational reorganization coupled with moderate electrostatic stabilization of zinc ion. The molecular weight is appropriate with the hydrophobic groups disposed outward for facile diffusion through the cell membrane. The compound will selectively remove zinc and copper ions from the human brain. Lead compound 3 is predicted to be a good starting point for the preventive drugs for Alzheimer's disease (AD).
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