D-peptide
{{Short description|Class of amino acids}}
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.{{cite journal |vauthors=Lacroix E, Viguera AR, Serrano L |date=April 1998 |title=Reading protein sequences backwards |journal=Folding & Design |volume=3 |issue=2 |pages=79–85 |doi=10.1016/S1359-0278(98)00013-3 |pmid=9565752 |doi-access=}} 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.{{cite journal |vauthors=Garton M, Nim S, Stone TA, Wang KE, Deber CM, Kim PM |date=February 2018 |title=Method to generate highly stable D-amino acid analogs of bioactive helical peptides using a mirror image of the entire PDB |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=115 |issue=7 |pages=1505–1510 |bibcode=2018PNAS..115.1505G |doi=10.1073/pnas.1711837115 |pmc=5816147 |pmid=29378946 |doi-access=free}}
File: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.{{cite journal |vauthors=Milton RC, Milton SC, Kent SB |year=1992 |title=Total chemical synthesis of a D-enzyme: the enantiomers of HIV-1 protease show demonstration of reciprocal chiral substrate specificity |journal=Science |volume=256 |issue=5062 |pages=1445–1448 |doi=10.1126/science.1604320 |pmid=1604320}}
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.{{cite journal |vauthors=Welch BD, VanDemark AP, Heroux A, Hill CP, Kay MS |date=October 2007 |title=Potent D-peptide inhibitors of HIV-1 entry |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=104 |issue=43 |pages=16828–33 |bibcode=2007PNAS..10416828W |doi=10.1073/pnas.0708109104 |pmc=2040420 |pmid=17942675 |doi-access=free}}
Ret design
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.{{cite journal |vauthors=Guichard G, Benkirane N, Zeder-Lutz G, van Regenmortel MH, Briand JP, Muller S |date=October 1994 |title=Antigenic mimicry of natural L-peptides with retro-inverso-peptidomimetics |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=91 |issue=21 |pages=9765–9 |bibcode=1994PNAS...91.9765G |doi=10.1073/pnas.91.21.9765 |pmc=44897 |pmid=7937888 |doi-access=free}}{{cite journal |vauthors=Cardó-Vila M, Giordano RJ, Sidman RL, Bronk LF, Fan Z, Mendelsohn J, Arap W, Pasqualini R |date=March 2010 |title=From combinatorial peptide selection to drug prototype (II): targeting the epidermal growth factor receptor pathway |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=107 |issue=11 |pages=5118–23 |bibcode=2010PNAS..107.5118C |doi=10.1073/pnas.0915146107 |pmc=2841862 |pmid=20190183 |doi-access=free}}
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.
Mirror-image phage display
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.{{cite journal |vauthors=Wiesehan K, Willbold D |date=September 2003 |title=Mirror-image Phage Display: Aiming at the Mirror |journal=ChemBioChem |volume=4 |issue=9 |pages=811–5 |doi=10.1002/cbic.200300570 |pmid=12964153 |s2cid=34014107}}{{cbignore|bot=medic}}
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.
References
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