Distorted Key Theory and Its Implication for Drug Development

Chou KC^1,2*

¹Gordon Life Science Institute, Boston, Massachusetts 02478, United States of America

²Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, China

*Corresponding author: Chou KC, Gordon Life Science Institute, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, China

Received: October 14, 2019; Accepted: October 25, 2019; Published: November 01, 2019

Abstract

During the last three decades or so, many efforts have been made to study the protein cleavage sites by some disease-causing enzyme, such as HIV (Human Immunodeficiency Virus) protease and SARS (Severe Acute Respiratory Syndrome) coronavirus main proteinase. It has become increasingly clear that the motivation of driving the aforementioned studies is quite wise, and that the results acquired through these studies are very rewarding, particularly for developing peptide drugs.

Keywords: HIV; SARS; Protein cleavage sites; Lock and key; Induced fit theory; Rack mechanism; Peptide drugs

Introduction

Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) is caused by infection with the Human Immunodeficiency Virus (HIV). Severe Acute Respiratory Syndrome (SARS) is a viral respiratory disease of zoonotic origin caused by the SARS coronavirus (SARS-CoV). Over the last two decades or so, many efforts have been made to study the protein cleavage sites by HIV protease (see, e.g., [1-25] and SARS coronavirus main proteinase [26-40]). Now it has become very clear that the motivation of driving the aforementioned studies is quite wise, and that the results acquired through these studies are very rewarding. Without losing generality, below let us consider the case of HIV protease.

Discussion

Functioning as a dimmer of two identical subunits, HIV protease has a crab-like shape (Figure. 1). 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 (Figure. 1); when in an inhibitor-binding state, the pincer-gate is closed, blocking the entrance.

Figure 1: 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. Adapted from [43] with permission.

    
    
    Figure 1: 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.
Adapted from [43] with permission.

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 (Figure. 2).

Figure 2: A schematic illustration to show a peptide in good fitting and tightly binding with the enzyme’s active site before it is cleaved by the latter. Adapted from [43] with permission.

    
    
    Figure 2: A schematic illustration to show a peptide in good fitting and tightly
binding with the enzyme’s active site before it is cleaved by the latter. Adapted
from [43] with permission.

According to Fisher’s “lock and key” model [41], Koshland’s “induced fit” theory and the “rack mechanism” [42], the prerequisite condition for a peptide to be cleaved by the disease-causing enzyme is a good fit and tightly binding with the enzyme’s active site (Figure. 2). However, such a peptide, after a modification on its scissile bond with some simple chemical procedure, will no longer be cleavable by the enzyme but it can still tightly bind to its active site. An illustration about the distorted key theory is given in (Figure. 3), where panel (a) shows an effective binding of a cleavable peptide to the active site of HIV protease, while panel (b) the peptide has become a non-cleavable one after its scissile bond is modified although it can still bind to the active site. Such a modified peptide, or ‘‘distorted key”, will automatically become an inhibitor candidate against HIV protease.

Figure 3: Schematic drawing to illustrate the “Distorted Key” theory, where panel (a) shows an effective binding of a cleavable peptide to the active site of a disease-causing enzyme, while panel (b) the same peptide has become a non-cleavable one after its scissile bond is modified although it can still bind to the active site. Such a modified peptide, or ‘‘distorted key”, will automatically become an inhibitor candidate against the disease-causing enzyme. Adapted from [43] with permission.

    
    
    Figure 3: Schematic drawing to illustrate the “Distorted Key” theory, where
panel (a) shows an effective binding of a cleavable peptide to the active site of
a disease-causing enzyme, while panel (b) the same peptide has become a
non-cleavable one after its scissile bond is modified although it can still bind to
the active site. Such a modified peptide, or ‘‘distorted key”, will automatically
become an inhibitor candidate against the disease-causing enzyme. Adapted
from [43] with permission.

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 in the sense of microenvironment. Besides, peptide drugs usually have no toxicity in vivo under the physiological concentration [28].

For more discussion about the distorted key theory, see a comprehensive review paper [43].

It was based on such a distorted key theory that many investigators were enthusiastic to develop various methods for predicting the protein cleavage sites by disease-causing enzymes (see, e.g., [2,5-8,10,11,13-16,20,21] and analyze them from the codon usage approach [1,44,45]).

Furthermore, a web-server called “HIVcleave” [21] has been established for predicting HIV protease cleavage sites in proteins. Its website address is at https://chou.med.harvard.edu/bioinf/HIV/.

For more discussions about the “distorted key theory”, see an insightful Wikipedia article at https://en.wikipedia.org/wiki/ Chou%27s_distorted_key_theory_for_peptide_drugs. To underscore the remarkable and awesome role in driving proteome and genome analyses, see [46-52], where a series of insightful recollections from different aspects have been clearly given.

Conclusion and Perspectives

Just like the pseudo amino acid components [53-56] and the 5-steps rule [57], which have been stimulated by the development of the sequence bioinformatics, widely and increasingly used in proteome and genome analysis [54, 57-230] and the guidelines for analyzing various biological systems [229-249], respectively, it is anticipated that the “distorted key theory” that was stimulated from the structural bioinformatics [250] as well as some pioneering studies [251-255] and their follow-up studies [42,44,256-282], will be also widely and increasingly used in drug development, particularly for developing peptide drugs [47] and multi-target drugs [46].

References

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Citation: Chou KC. Distorted Key Theory and Its Implication for Drug Development. Austin Biochem. 2019; 4(1): 1023.

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