A D-peptide is a small sequence of D-amino acids. Since ribosomes are specific to L-amino acids, D-peptides rarely occur naturally in organisms and are not easily digested or degraded. D-peptide peptidomimetics are D-peptides designed to mimic natural L-peptides that commonly have therapeutic properties. A peptide with secondary structure cannot be mimicked by its retro-inverse, as linking in the reverse order breaks many backbone interactions essential for the secondary structure.[1] An approach to mimicking these peptides is by searching for similar (sidechain) structures in a mirrored copy of the Protein Data Bank for the structured elements, and then linking the sections by retro-inversed versions of the loops found in the original protein.[2]
![L-Peptide Asp-Val-Ser and its mirror image.](https://upload.wikimedia.org/wikipedia/commons/thumb/1/15/L-Peptide-D-PeptideMirrorImages.png/300px-L-Peptide-D-PeptideMirrorImages.png)
When placed in a nonchiral solvent like water, D-peptides, as well as the larger polypeptide D-proteins, have similar but mirrored properties to the L-peptides and L-proteins with identical sequences. If an L-protein does not require a chaperone or a structural cofactor to fold, its D-enantiomer protein should have a mirror image conformation with respect to the L-protein (Figure 2). A D-enzyme should act on substrates of reverse chirality compared to the L-enzyme with the same sequence. Similarly, if an L-peptide binds to an L-protein, their D-peptide and D-protein counterparts should bind together in a mirrored way.[3]
D-peptides also have properties that make them attractive as drugs. D-peptides are less susceptible to be degraded in the stomach or inside cells by proteolysis. D-peptide drugs can, therefore, be taken orally and are effective for a longer period of time. D-peptides are easy to synthesize when compared to many other drugs. In some cases, D-peptides can have a low immunogenic response.[4]
Ret design
[edit]An L-peptide has three analogue sequences (Figure 3) built from L and D amino acids: the D-enantiomer or inverso-peptide with the same sequence, but composed of D-amino acids and a mirror conformation; the retro-peptide, consisting of the same sequence of L amino acids but in reverse order; and the retro-inverso or D-retro-enantiomer peptide, consisting of D-amino acids in the reversed sequence.[5][6]
While the L-peptide and its D-enantiomer are mirror structures of each other, the L-retro-peptide is the mirror image of the D-retro-inverso-peptide. On the other hand, the L-peptide and the D-retro-inverso-peptide share a similar arrangement of side-chains, although their carboxyl and amino groups point in opposing directions. For small peptides that do not depend on a secondary structure for binding, an L-peptide and its D-retro-inverso-peptide is likely to have a similar binding affinity with a target L-protein.
![A fragment sequence and its analogues.](https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/L-peptideD-peptideAnalogues.png/300px-L-peptideD-peptideAnalogues.png)
Mirror-image phage display
[edit]Phage display is a technique to screen large libraries of peptides for binding to a target protein. In phage display, the DNA sequence that codes the potential drug-peptide is fused to the gene of the protein coat of bacteriophages and introduced into a vector. Diversity can be introduced to the peptide by mutagenesis. The protein coats peptides are then expressed and purified, and applied to a surface of immobilized protein targets. The surface is then washed away to remove non-binding peptides, while the remaining binding peptides are eluted.[7]
Mirror-image phage display is a similar method that can be used to screen large libraries of D-peptides that bind to target L-proteins. More precisely, since D-peptides can not be expressed in bacteriophages, mirror-image phage display screens L-peptides that bind to immobilized D-proteins that are previously chemically synthesized. Because of the mirror properties of D-peptides, the D-enantiomer of an L-peptide that binds to a D-protein will bind to the L-protein.
Mirror-image phage display, however, has two disadvantages when compared to phage display. Target D-proteins must be chemically synthesized, which is normally an expensive and time-consuming process. Also, the target protein must not require a cofactor or a chaperone to fold, otherwise the chemically synthesized D-protein will not fold to the target, mirror structure.
![](https://upload.wikimedia.org/wikipedia/commons/thumb/5/59/MirrorImagePhageDisplay.png/500px-MirrorImagePhageDisplay.png)
References
[edit]- ^ Lacroix E, Viguera AR, Serrano L (April 1998). "Reading protein sequences backwards". Folding & Design. 3 (2): 79–85. doi:10.1016/S1359-0278(98)00013-3. PMID 9565752.
- ^ Garton M, Nim S, Stone TA, Wang KE, Deber CM, Kim PM (February 2018). "Method to generate highly stable D-amino acid analogs of bioactive helical peptides using a mirror image of the entire PDB". Proceedings of the National Academy of Sciences of the United States of America. 115 (7): 1505–1510. Bibcode:2018PNAS..115.1505G. doi:10.1073/pnas.1711837115. PMC 5816147. PMID 29378946.
- ^ Milton RC, Milton SC, Kent SB (1992). "Total chemical synthesis of a D-enzyme: the enantiomers of HIV-1 protease show demonstration of reciprocal chiral substrate specificity". Science. 256 (5062): 1445–1448. doi:10.1126/science.1604320. PMID 1604320.
- ^ Welch BD, VanDemark AP, Heroux A, Hill CP, Kay MS (October 2007). "Potent D-peptide inhibitors of HIV-1 entry". Proceedings of the National Academy of Sciences of the United States of America. 104 (43): 16828–33. Bibcode:2007PNAS..10416828W. doi:10.1073/pnas.0708109104. PMC 2040420. PMID 17942675.
- ^ Guichard G, Benkirane N, Zeder-Lutz G, van Regenmortel MH, Briand JP, Muller S (October 1994). "Antigenic mimicry of natural L-peptides with retro-inverso-peptidomimetics". Proceedings of the National Academy of Sciences of the United States of America. 91 (21): 9765–9. Bibcode:1994PNAS...91.9765G. doi:10.1073/pnas.91.21.9765. PMC 44897. PMID 7937888.
- ^ Cardó-Vila M, Giordano RJ, Sidman RL, Bronk LF, Fan Z, Mendelsohn J, Arap W, Pasqualini R (March 2010). "From combinatorial peptide selection to drug prototype (II): targeting the epidermal growth factor receptor pathway". Proceedings of the National Academy of Sciences of the United States of America. 107 (11): 5118–23. Bibcode:2010PNAS..107.5118C. doi:10.1073/pnas.0915146107. PMC 2841862. PMID 20190183.
- ^ Wiesehan K, Willbold D (September 2003). "Mirror-image Phage Display: Aiming at the Mirror". ChemBioChem. 4 (9): 811–5. doi:10.1002/cbic.200300570. PMID 12964153. S2CID 34014107.
Well, that’s interesting to know that Psilotum nudum are known as whisk ferns. Psilotum nudum is the commoner species of the two. While the P. flaccidum is a rare species and is found in the tropical islands. Both the species are usually epiphytic in habit and grow upon tree ferns. These species may also be terrestrial and grow in humus or in the crevices of the rocks.
View the detailed Guide of Psilotum nudum: Detailed Study Of Psilotum Nudum (Whisk Fern), Classification, Anatomy, Reproduction