Deciphering the conformational landscape of few selected aromatic noncoded amino acids (NCAAs) for applications in rational design of peptide therapeutics

Abstract

Amino acids are the essential building blocks of both synthetic and natural peptides, which are crucial for biological functions and also important as biological probes for mapping the complex protein–protein interactions (PPIs) in both prokaryotic and eukaryotic systems. Mapping the PPIs through the chemical biology approach provides pharmacologically relevant peptides, which can have agonistic or antagonistic effects on the targeted biological systems. It is evidenced that ≥ 60 peptide-based drugs have been approved by the US-FDA so far, and the number will improve further in the foreseeable future, as ≥ 140 peptides are currently in clinical trials. However, natural peptides often require fine-tuning of their pharmacological properties by strategically replacing the α L -amino acids of the peptides with non-coded amino acids (NCAA), for which codons are absent in the genetic code for biosynthesis of proteins, prior to their applications as therapeutics. Considering the diverse repertoire of the NCAAs, the conformational space of many NCAAs is yet to be explored systematically in the context of the rational design of therapeutic peptides. The current study deciphers the conformational landscape of a few such Cα-substituted aromatic NCAAs (Ing: 2-indanyl- l -Glycine; Bpa: 4-benzoyl- l -phenylalanine; Aic: 2-aminoindane-2-carboxylic acid) both in the context of tripeptides and model synthetic peptide sequences, using alanine (Ala) and proline (Pro) as the reference. The combined data obtained from the computational and biophysical studies indicate the general success of this approach, which can be exploited further to rationally design optimized peptide sequences of unusual architecture with potent antimicrobial, antiviral, gluco-regulatory, immunomodulatory, and anti-inflammatory activities. Supplementary Information The online version contains supplementary material available at 10.1007/s00726-022-03175-z.

Neutraligands of C5a can potentially occlude the interaction of C5a with the complement receptors C5aR1 and C5aR2

“…Alternatively, trapping and sequestering of C5a from its receptors can be achieved by targeting the combined hotspots surface area on C5a by antibody-like small designer peptides. 36 In this context, as elaborated earlier and presented in Figure 11, small-molecule drugs such as raloxifene 19 and prednisone 18 can occupy crucial binding sites on the surface of C5a and alter its biologically active conformation. As a result, binding of the C5a to the complement receptors will not be effective and, thus, C5a-triggered pathological signaling of the receptors can be modulated.…”

“…From a therapeutic drug‐screening standpoint, the hotspot areas on C5a 17 interacting with the aspartates on the NT‐peptide of C5aR1 or C5aR2 can be sequestered by selective targeting through drug repurposing or by designing new chemical entities. Alternatively, trapping and sequestering of C5a from its receptors can be achieved by targeting the combined hotspots surface area on C5a by antibody‐like small designer peptides 36 . In this context, as elaborated earlier and presented in Figure 11, small‐molecule drugs such as raloxifene 19 and prednisone 18 can occupy crucial binding sites on the surface of C5a and alter its biologically active conformation.…”

Novel Crown Ether Amino Acids as Fluorescent Reporters for Metal Ions

“…Furan and thiophene are electron donor heterocycles tha tribute to the overall conjugation and provide additional binding sites for catio expected that additional non-covalent interactions with the O and S heteroatom play a synergetic role in differentiating soft transition metal cations. The structures of the crown ether aldehydes 1a,c-e were confirmed by 1 H and 13 C NMR spectroscopy with the characteristic formyl group signals appearing in the range o 9.61-10.00 ppm (for 1 H) and 181.00-191.76 ppm (for 13 C). The NMR of compound 1c was in accordance with the previously published assignment [31].…”

“…The structures of the crown ether aldehydes 1a,c-e were confirmed by 1 H and 13 C NMR spectroscopy with the characteristic formyl group signals appearing in the range of 9.61-10.00 ppm (for 1 H) and 181.00-191.76 ppm (for 13 C). The NMR of compound 1c was in accordance with the previously published assignment [31].…”

“…Synthetic unnatural amino acids can be a source of structural diversity and functional versatility and are often used as building blocks and molecular scaffolds in the construction of peptide and proteins with tailored properties [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Recently, systems incorporating unnatural amino acids have been reported in applications as diverse as probes for the regulation of enzyme activity and conformational studies [1-3], sensors and biosensors, reservoirs of metal binding motifs in metabolically stable and biologically active molecules [4,5], the targeting of peptides for molecular imaging [6][7][8], peptide drug candidates with better selectivity, activity, and lower toxicity [9][10][11][12][13], and in enzyme engineering for tuning and expanding the structural and functional features of unnatural amino acids [14][15][16] and catalysts [17] via site-specific incorporation, among many other examples.…”