D-peptides have a lot of therapeutic potential because they are more resistant to degradation than their L-enantiomeric counterparts. L-peptides are often quickly cleaved into their amino acid substituents in the body, making them poor curative agents. Most proteases are chiral, so they can distinguish between L- and D-enantiomeric versions of the substrate; as a result, D-peptides are able to resist the activity of proteases.
Figure 1. Active site of SIV protease. Cleaved peptide is in orange while key active site residues are in yellow (PDB: 1YTG [24]).
Chymotrypsin Mechanism
Figure 2. Active site of chymotrypsin. Ser and Gly make the oxyanion hole while another Ser, His, and Asp make the catalytic triad.
There are many different proteases in the human body, each one using a different amino acid side chain to cleave peptide bonds. One of the most prevalent ones is the serine protease, which uses a serine residue and a catalytic triad to facilitate the reaction. Chymotrypsin, a common serine protease, hosts a trio of histidine, aspartate, and serine residues as its catalytic triad [7]. In addition to the triad, the active site of chymotrypsin also features an oxyanion hole, which is a pocket of positive charge that stabilizes the oxyanion of the substrate intermediate. Peptide bond hydrolysis is generally an unfavorable reaction so as with all enzymes, chymotrypsin helps overcome some energetic barriers.
Figure 3. Mechanism of chymotrypsin. The peptide is stabilized by the oxyanion hole and the catalytic triad facilitates the reaction.
In addition to disrupting the peptide bond with a serine, chymotrypsin does three other important things: activate the amide bond for nucleophilic attack, activate water to make it a good nucleophile, and protonate the amine to make it a good leaving group. The result of these actions makes peptide hydrolysis occur approximately 1010 faster than when it is uncatalyzed [7]. The reaction occurs in the following steps:
- A histidine residue deprotonates a serine residue, which attacks the carbonyl of the substrate, forming a tetrahedral intermediate. This links the enzyme and substrate covalently.
- The same histidine residue donates a proton to the amide as that portion of the peptide leaves, and the carbonyl reforms.
- The histidine residue now abstracts a proton from water, allowing the resulting hydroxide to attack the carbonyl. This creates another tetrahedral intermediate.
- This serine residue is kicked off and protonated by the histidine residue, reforming the carbonyl again.
- The other portion of the peptide disassociates from the active site,
In this reaction, the serine is the only residue that interacts covalently with the substrate, while the histidine residue serves a proton shuttle. Another residue, an aspartate, stabilizes the histidine throughout the reaction and completes the catalytic triad.
Chymotrypsin specificity
Proteases are extremely specific for their substrates, and often feature form different interacts with the peptides to stabilize them in the active site. Chymotrypsin presents up to nine different recognition sites that interact with specific substrate side chains: therefore, it is very specific for the types of amino acid residues it cleaves. Some of the important recognition sites are:
- The S1 and S2 sites which favors hydrophobic P1 and P2 side chains, where P1 and P2 are the first two residues on the acyl side of the cleaved peptide bond.
- Asp35 and Asp64 which form electrostatic interactions with P1′ – Arg or Lys side chains, where P1′ is the first residue on the leaving group side of the cleaved peptide bond.
- Residues 214 to 216 which form antiparallel beta sheet with P1 to P3 via hydrogen bonds.
Figure 4. Active site of chymotrypsin. The S1 and S2 recognition sites are aligned with the P1 and P2 side chains. Asp35 and Asp64 interact with a specific P1′ side chain. Residues 215 to 217 form a beta sheet with the peptide via hydrogen bonds. X marks the cleavage site.
Chymotrypsin with D-peptides
Given the extreme specificity of proteases, it is easy to see why D-peptides might be resistant to degradation. There are numerous interactions between the active site residues and substrate backbone that are likely compromised when the substrate is in a D-enantiomeric form. There are also direct interactions with the substrate’s side chains as well, so if they are not oriented correctly, the substrate would not be stable in the active site. These are just assumptions however, and experimental evidence is needed to verify them.
In one study, L- and D- enantiomeric forms of a short polypeptide were incubated with a variety of proteases, including chymotrypsin [6]. Results were quantified by the reaction of peptide amines with a fluorescent indicator. The amount of L- and D-peptides digested was reported as fractions of the total peptides incubated.
Figure 5. L- and D-peptide digestion by proteases. Open circles represent L-peptides, closed circles represent D-peptides. A: carboxypeptidase, B: papain, C: pepsin, D: trypsin, E: elastase, F: chymotrypsin. Reproduced with permission from publisher from reference 6. © 1995 John Wiley & Sons, Inc.
The results from the study show that with all proteases, D-peptides were cleaved significantly less than the L-peptides. With chymotrypsin specifically, about half the amount of L-peptides were cleaved, while only about 10% of the D-peptides were degraded. These data reinforce the idea that proteases are extremely specific for their substrates. In the case of chymotrypsin however, it is possible that its active site is a little more lenient in terms of specificity. Sterics are likely the reason for this selectivity: an example is shown with a D-peptide instead of a L-peptide in the active site of chymotrypsin.
Figure 6. Active site of chymotrypsin with a D-peptide. It is possible that a D-peptide would never even make it into the active site, but if it does, many of the interactions that stabilize the substrate would not be possible. The S1 and S2 sites would also not recognize the P1 and P2 side chains.
While this figure shows a D-peptide inside the active site, it is believed that this is not a favorable complex. The D-peptide does not stay very long in the active site however, because of its poor stability due to lack of interactions. The mechanism of peptide cleavage likely still works with a D-peptide however, as shown by the experimental evidence (Fig. 5). In short, it is the lack of stability in the active site rather than mechanism hindrance that confers the D-peptide’s proteolytic resistance.
I like the organization of this webpage. Stating the normal mechanism of action for chymotrypsin and following it up with what specifically goes wrong in attempting to hydrolyze D-peptides, complete with detailed mechanistic figures, is a helpful comparison that very well highlights the advantage of D-peptides for drug development. While there is conceptual evidence that D-peptides are not suitable substrates for proteases, I’m curious if there has been an experiments done confirming this L specificity of proteases. If so, those result would be neat additions to further support the D-peptide protease resistance.
I’m also wondering how D-peptides respond to other types of proteases, like aspartyl proteases, which are not as specific as serine proteases that use the catalytic triad and stabilizing hydrophobic pocket.
I agree with everything Suraj said. This page is extremely detailed, easy to read, and informative. Besides Suraj’s questions, there really isn’t much to add here! Well done!
Thanks for sharing detailed information.
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