Enhanced Permeability and Binding Activity of Isobutylene‐Grafted Peptides

Abstract

We present a new peptide‐macrocyclization strategy with an isobutylene graft. The reaction is mild and proceeds rapidly and efficiently both for linear and cyclic peptides. The resulting isobutylene‐grafted peptides possess improved passive membrane permeability due to the shielding of the polar backbone of the amides, as demonstrated by NMR spectroscopy and molecular dynamics simulations. The isobutylene‐stapled structures are fully stable in human plasma and in the presence of glutathione. This strategy can be applied to bioactive cyclic peptides such as somatostatin. Importantly, we found that structural preorganization forced by the isobutylene graft leads to a significant improvement in binding. The combined advantages of directness, selectivity, and smallness could allow application to peptide macrocyclization based on this attachment of the isobutylene graft.

Radical‐Mediated Thiol‐Ene Strategy: Photoactivation of Thiol‐Containing Drugs in Cancer Cells

“…Inspired by this AFCT reaction, we hypothesized that the the isobutylene structure could be used as a bridging graft to cage thiol‐containing drugs and allow further controlled activation of anticancer drugs by means of a radical‐mediated thiol‐ene mechanism (Scheme ). Previously, we reported a one‐pot macrocyclization strategy [with tris(2‐carboxyethyl)phosphine (TCEP)] for thiol‐containing peptides by using an isobutylene graft, which can significantly enhance both membrane permeability and binding activity of the corresponding macrocycles . The isobutylene graft can be rapidly and efficiently installed onto reduced thiol groups in a biocompatible manner because of the high reactivity of the bis(bromo)isobutylene.…”

“…Moreover, the reaction was also rapid and efficient when glutathione was used as a thiol source in a mixture of DMF and water as the solvent, which shows that the reaction is practical for an aqueous environment. Then, the feasibility of our strategy was investigated with an isobutylene cyclized 5‐mer peptide that bears two terminal cysteines and was synthesized by solid‐phase peptide synthesis . The short peptide was completely converted into the disulfide derivative within 15 minutes under the same reaction conditions described previously (Figure ).…”

A Physical Organic Approach to Tuning Reagents for Selective and Stable Methionine Bioconjugation

“…In this context, we pursued an application in peptide stapling, where bioconjugate stability plays an important role in the overall performance of the resulting macrocyclic peptide for various applications. [20][21][22][23] Peptide stapling methods often require pre-functionalization of amino acid residues, incorporation of non-natural amino acids, reactions performed in non-aqueous media, or protection of reactive residues before stapling. 20,21,24,25 We reasoned that the high chemoselectivity of the ReACT method for methionine labeling, even in the presence of competing reactive nucleophiles such as tryptophan and lysine, along with gains in stability, would provide a unique and attractive technology for peptide stapling that could circumvent many of the above-mentioned limitations.…”

Radical‐Mediated Thiol‐Ene Strategy: Photoactivation of Thiol‐Containing Drugs in Cancer Cells

“…Then, the feasibility of our strategy was investigated with an isobutylene cyclized 5-mer peptide that bears two terminal cysteines and was synthesized by solidphase peptide synthesis. [13] Theshort peptide was completely converted into the disulfide derivative within 15 minutes under the same reaction conditions described previously (Figure 1).…”

“…Previously,w er eported ao ne-pot macrocyclization strategy [with tris(2-carboxyethyl)phosphine (TCEP)] for thiol-containing peptides by [*] S. Sun using an isobutylene graft, which can significantly enhance both membrane permeability and binding activity of the corresponding macrocycles. [13] Thei sobutylene graft can be rapidly and efficiently installed onto reduced thiol groups in abiocompatible manner because of the high reactivity of the bis(bromo)isobutylene.O ur research began with N-tertbutoxycarbonyl-l-cysteine methyl ester (N-Boc-Cys-OMe 1), which was protected with 3-bromo-2-bromomethyl-1propene (Table 1a nd Supporting Information). Thes tapled cysteine 2 was then screened under as eries of reaction conditions.F irstly,d ifferent PIs were tested with the same amounts of thiol source,1 -thio-b-d-glucose tetraacetate (4AcGlcSH), and 2 under irradiation at 365 nm.…”