人の長寿と長生きの抗酸菌；抗酸菌がゆっくりと生きて頻繁に眠るしくみから、薬剤開発への展開を考える

<p>  Research that responds to the desire to live longer and be healthier has led to the discovery of life extention through calorie restriction. Interestingly, this mechanism is conserved from nematodes to mice to primates. Important molecular mechanisms for this longevity effect is the suppression of gene expression and metabolism, including respiration, through upregulation of sirtuin genes and suppression of mTOR signaling. </p><p>  Cells can rejuvenate by dividing. Since bacteria are infinitely dividing cells, they have no lifespan. Bacteria, however, cannot always divide in the real world and fall into a situation where they have to endure. Such bacteria are called persisters. A thorny problem in medicine is the presence of drug persisters. Mycobacteria are particularly well resistant to medication. Mycobacteria tend to persisters. </p><p>  Mycobacteria produce Mycobacterial DNA-binding protein 1 (MDP1). MDP1 is an intrinsically disorder protein (IDP) that represses transcription and proliferation by the intrinsically disorder region (IDR). MDP1 also induces tolerance to the isoniazid, phenotype of dormant M. tuberculosis by suppressing the expression of the isoniazid-activating enzyme KatG. Thus MDP1 induces persisters of mycobacteria. </p><p>  As the function of MDP1 became clear, I was aware the overlap between the activity of MDP1 and the mechanism of longevity in eukaryotes. It is interesting that there are many commonalities in the mechanisms by which even cells that cannot divide and would normally age and reach the end of their life span continue to live. </p><p>  If the function of MDP1 can be suppressed, it can be expected to shorten the period of disease treatment. Drugs that can inhibit the function of IDR are candidates for this. IDPs deviate from the classical ‘lock and key’ model of protein binding and have been excluded as drug targets in traditional drug discovery. </p><p>  In human, misfolding of IDPs causes cancer and intractable diseases such as Alzheimer’s disease. It can be said that difficulty of drug discovery against IDP/IDR is the reason for causing the intractable diseases. </p><p>  If we can establish way of drug discovery method against IDP/IDR, it may be possible to shorten the treatment period for mycobacterial diseases, and it will open the way to treatments for intractable diseases such as cancer and neurodegenerative diseases. Targeting molecules with inconsistent structures will not be easy, but it is a challenge that science must overcome.</p>