NS  Vol.12 No.9 , September 2020
The Significant and Profound Impacts of Chou’s Distorted Key Theory for Developing Peptide Drugs
Abstract: In this short review paper, the significant and profound impacts of the distorted key theory for developing peptide drugs have been briefly recalled with crystal clear convincingness.

As a culprit of AIDS [1], HIV protease has been a target for developing drugs against AIDS [2]. Functioning as a dimmer of two identical subunits, HIV protease has a crab-like shape. Its catalytic cleft is gated by a pair of flaps (or pincers if viewed as a crab). When the enzyme is in an inhibitor-free state, the pincer-gate is open, allowing substrates to enter the catalytic cleft; when in an inhibitor-binding state, the pincer-gate is closed, blocking the entrance [3]. As a member of the aspartyl proteases, HIV protease is highly substrate-selective and cleavage-specific. Its susceptible sites in a protein extend to an octapeptide region [4].

Knowledge of the protein cleavage sites by HIV protease can provide very useful information for finding effective inhibitors against the culprit enzyme, as elaborated by Kuo-Chen Chou in [5].

According to Fisher’s lock-and-key model proposed by Hermann Emil Fischer in 1984 and Koshland’s induced fit theory by Daniel E. Koshland, Jr. in 1958, given a peptide, the prerequisite condition for it to be cleaved by HIV-protease is a good fit and binding between the substrate and the enzyme’s active site. However, such a peptide, after a modification on its scissile bond with some simple chemical procedure, will completely lose its cleavability but it can still tightly bind to the enzyme’s active site. According to Kuo-Chen Chou [3], the molecule thus modified can be likened to a “distorted key”, which can be inserted into a lock but can neither open the lock nor automatically get out from it. That is why a molecule modified from a cleavable peptide can spontaneously become a competitive inhibitor against the enzyme [6].

Even for non-peptide inhibitors, the information derived from the cleavable peptides can also provide useful insights about the key binding groups and fitting conformation, among many other detailed requirements in microenvironment.

Many efforts have been made to predict the protein cleavage sites by HIV-protease (see, e.g., [6-8]). Also, a webserver named HIVcleave was established [9] for predicting HIV protease cleavage sites in proteins.

Furthermore, Chou’s distorted key theory was also utilized to develop inhibitors against severe acute respiratory syndrome (SARS) (see, e.g., [10-12]).

Cite this paper: Chou, K. (2020) The Significant and Profound Impacts of Chou’s Distorted Key Theory for Developing Peptide Drugs. Natural Science, 12, 638-639. doi: 10.4236/ns.2020.129049.

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