BACE inhibitors
Several different types of BACE inhibitors have been synthesized and screened for their activities. Clinically useful BACE inhibitors are yet to develop due to the challenges faced during drug design. Peptidomimetic transition state analogs as shown in Figure 1 are one of the most well studied compounds (Citron, 2004).
How do peptidomimetic transition state analogs (PTSA) work?
Evaluation
Some Challenges faced in developing PTSA
How novel is the discovery of BACE inhibitors?
It is the first time the idea of transition state analogues is applied for the treatment of AD. The activity of BACE has been discovered for a while, but its function has only been validated in humans recently by the protective mutation, A673T, of the APP gene. This makes the discovery of BACE inhibitors novel as to inhibit the formation of amyloid plaques.
Is it truly a medical breakthrough?
Yes. Although currently there are challenges that prevent them to be developed into clinically useful drugs and they cannot cure the disease completely, the studies provide insights into the activities of the PTSA as a result of structural differences. This forms the basis of better optimized drugs that can slow down the progression of AD.
Several different types of BACE inhibitors have been synthesized and screened for their activities. Clinically useful BACE inhibitors are yet to develop due to the challenges faced during drug design. Peptidomimetic transition state analogs as shown in Figure 1 are one of the most well studied compounds (Citron, 2004).
How do peptidomimetic transition state analogs (PTSA) work?
- Mimic the transition state analog of BACE with part of the compound binds to the active site of the enzyme
- As enzyme binds transition state more tightly than the endogenous substrate(s), the enzyme is effectively inhibited.
- APP cleavage by BACE is inhibited.
Evaluation
Some Challenges faced in developing PTSA
- Cost: It is always expensive to design a drug.
- Blood brain barrier (BBB) penetration: Brain is very versatile in protecting against the entry of foreign substances as a protective mechanism. However, the barrier presents difficulties when we are trying to deliver the BACE inhibitors to the brain to treat AD.
- Very importantly, it cannot cure AD completely and it only slow down its progression! BACE inhibitors can at best prevent the formation of more beta-amyloid plaques that advances the disease, but the function of the brain regions that have already been destroyed cannot be reversed. As we all know, neurons have very limited ability to regenerate.
How novel is the discovery of BACE inhibitors?
It is the first time the idea of transition state analogues is applied for the treatment of AD. The activity of BACE has been discovered for a while, but its function has only been validated in humans recently by the protective mutation, A673T, of the APP gene. This makes the discovery of BACE inhibitors novel as to inhibit the formation of amyloid plaques.
Is it truly a medical breakthrough?
Yes. Although currently there are challenges that prevent them to be developed into clinically useful drugs and they cannot cure the disease completely, the studies provide insights into the activities of the PTSA as a result of structural differences. This forms the basis of better optimized drugs that can slow down the progression of AD.
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