PEPlife: A Repository of the Half-life of Peptides

Abstract

Short half-life is one of the key challenges in the field of therapeutic peptides. Various studies have reported enhancement in the stability of peptides using methods like chemical modifications, D-amino acid substitution, cyclization, replacement of labile aminos acids, etc. In order to study this scattered data, there is a pressing need for a repository dedicated to the half-life of peptides. To fill this lacuna, we have developed PEPlife (http://crdd.osdd.net/raghava/peplife), a manually curated resource of experimentally determined half-life of peptides. PEPlife contains 2229 entries covering 1193 unique peptides. Each entry provides detailed information of the peptide, like its name, sequence, half-life, modifications, the experimental assay for determining half-life, biological nature and activity of the peptide. We also maintain SMILES and structures of peptides. We have incorporated web-based modules to offer user-friendly data searching and browsing in the database. PEPlife integrates numerous tools to perform various types of analysis such as BLAST, Smith-Waterman algorithm, GGSEARCH, Jalview and MUSTANG. PEPlife would augment the understanding of different factors that affect the half-life of peptides like modifications, sequence, length, route of delivery of the peptide, etc. We anticipate that PEPlife will be useful for the researchers working in the area of peptide-based therapeutics.

Toward a Novel Drug To Target the EGF–EGFR Interaction: Design of Metabolically Stable Bicyclic Peptides

“…Being an all‐ l ‐peptide, our first EGF–EGFR inhibitor, cp28, was predictably labile in vivo. In fact, in human serum, cp28 showed a half‐life of 89 min, which is reasonable for a natural peptide (the half‐life of a linear peptide is typically less than 30 min) . To identify the main cleavage sites on the sequence of cp28, we performed MS–MS analysis of the serum sample after incubating for 2 h. Interestingly, the three main metabolites resulted from hydrolysis and/or oxidation of Arg23 and Met24 (Figure S10), a region in which the peptide chain adopts a rather extended conformation and is thus more accessible to the active site of proteolytic enzymes.…”

Immunoinformatic and dynamic simulation-based designing of a multi-epitope vaccine against emerging pathogen Elizabethkingia anophelis

“…Furthermore, the aliphatic index and instability index classify our vaccine as thermostable, while the negative GRAVY value suggests that the vaccine protein is hydrophilic and has strong interactions with water molecules. However, one of the biggest drawbacks in the field of therapeutic proteins is the short halflife of peptides 40 . Interestingly, our vaccine protein half-life in mammalian reticulocytes (in vitro) was 30 hours and more than 20 hours and 10 hours in yeast and E. coli cells in vivo, respectively which is satisfactory based on earlier findings 34,35 .…”

Designed Macrocyclic Peptides as Nanomolar Amyloid Inhibitors Based on Minimal Recognition Elements

“…First, analogue 2c with three d-Arg residues in the linker region instead three l-Arg residues was synthesized, followed by 2d, in which, in addition, Phe and Leu residues were replaced with d residues.However,t he t 1/2 values were only slightly improved (ca. [11] We next investigated whether the switching of chirality affected the structure and function of the peptides as compared to 2b.T he shapes of the CD spectra of 2c-e were similar to that of 2b, but their minima were blue-shifted, indicative of different types of turns and/or bstrand content (Figure 2f;s ee also Figure S10). We therefore synthesized 2e, in which additionally the two l-Cys residues were replaced with d-Cys.I mportantly, 2e exhibited highly improved proteolytic stability also in comparison to other peptides (t 1/2 > 11 h), being more than 30-fold more resistant than 1 (t 1/2 % 20 min) and more than 15-fold more resistant than its l analogue 2b (t 1/2 % 45 min;F igure 3a;s ee also Figure S9).…”

“…[7a, 8] In fact, the formation of high-affinity nonfibrillar IAPP-Ab40(42) heteroassemblies has been shown to suppress Ab40(42) amyloid self-assembly. [4,9] Accordingly,w eh ave recently designed linear peptides mimicking putative IAPP self-/cross-interaction surfaces (called "interaction surface mimics" (ISMs)) by linking IAPP (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) with double Nmethylated IAPP(22-28) using different tripeptide units. [4,9] Accordingly,w eh ave recently designed linear peptides mimicking putative IAPP self-/cross-interaction surfaces (called "interaction surface mimics" (ISMs)) by linking IAPP (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) with double Nmethylated IAPP(22-28) using different tripeptide units.…”

“…To reduce the size of 1,w es ynthesized its analogue 2 lacking the region IAPP (8)(9)(10)(11)(12)(13). N-terminal truncation was based on the suggestion that IAPP(14-18) and IAPP(22-28) mediate key interactions for both IAPP self-and heteroassembly.…”