Protocol for efficient solid-phase synthesis of peptides containing 1-hydroxypyridine-2-one (1,2-HOPO)

Highlights • Metal chelation has found many applications that directly affect human's life. • Natural siderophores are one of the most potent chelators for Fe (III) • 1-Hydroxypyridine-2-one (1,2-HOPO) (Fig. 1a), which is shown in 4-carboxy-1-hydroxypyridin-2-one (1,2-HOPO-4-COOH) (Fig. 1b), is a moiety that electronically resembles the hydroxamate group found in natural siderophores (Fig. 1c). Of note, 1,2-HOPO moiety is present in the natural siderophore cepabactin [1] • Synthesis of 1,2-HOPO containing chelators has been carried in solid phase using carboxylic acid derivatives of 1,2-HOPO and required the protection of the reactive hydroxyl group usually with benzyl group (Bzl). After the peptide elongation, the Bzl group has been removed on the same solid phase using a bit harsh conditions: 0.1 M BBr3 in DCM for 60 min [2], 10% HBr in AcOH for 14 h [3]; in solution: 1 M BCl3 in DCM for 2 d [4], 50% HCl in AcOH for 4 d [5], H2-Pd/C, AcOH-MeOH [6]. • First of all, a method for the incorporation of the 1,2-HOPO-4-COOH through its carboxyl group into the peptide backbone without protecting the N-OH is proposed (the presence of the carboxyl group facilitates the attachment). • Furthermore, in the cases that Bzl protection is required for the N-OH, a friendlier method for removing the Bzl is described. The removal of the Bzl is done concomitantly to the global deprotection and cleavage of the peptide from the resin using TFA- TFMSA-H2O (8:3:1).The work was funded in part by the following: the National Research Foundation (NRF) (# 105892 and Blue Sky's Research Programme # 120386) and the University of KwaZulu-Natal (South Africa); and the Spanish Ministry of Science, Innovation, and Universities (RTI2018-093831-B-100), the Generalitat de Catalunya (2017 SGR 1439) (Spain), and Marató TV3 foundation 2018 (#20183530). We thank Professor Miquel Viñas (University of Barcelona) for fruitful discussions. XX The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.Peer reviewe

Solid-phase synthesis of peptides containing 1-Hydroxypyridine-2-one (1,2-HOPO)

Herein a friendly method for the preparation of 1-hydroxypyridine-2-one (1,2-HOPO)-containing peptides is described. The elongation of the peptide is carried out on a solid support, using a protecting group for the ε-amino of the Lys that is removable in very mild conditions and that does not provoke cleavage of the peptide from the resin. Once the ε-amino of the Lys is released, HOPO can be incorporated using a commercially available derivative (1,2-HOPO-4-COOH), which has a carboxylic acid at position 4 of the aromatic ring. 1,2-HOPO-4-COOH can be introduced with the free N-hydroxyl or protected with the benzyl group. The former is recommended in many cases. If the protected derivative is to be used, the benzyl group can be removed during global deprotection and cleavage from the resin by adding trifluoromethanesulfonic acid to the cleavage cocktail.The work was funded in part by the following: the National Research Foundation, South Africa (NRF) (# 105892 and Blue Sky’s Research Programme # 120386) and the University of KwaZulu-Natal (South Africa); and the Spanish Ministry of Science, Innovation, and Universities (RTI2018-093831-B-100), the Generalitat de Catalunya (2017 SGR 1439) (Spain), and Marató TV3 foundation 2018 (#20183530). We thank Professor Miquel Viñas (University of Barcelona) for fruitful discussions

2023 FDA TIDES (Peptides and Oligonucleotides) Harvest

A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of disorders, including amyotrophic lateral sclerosis, geographic atrophy, primary hyperoxaluria type 1, and polyneuropathy of hereditary transthyretin-mediated amyloidosis. All oligonucleotides show chemically modified structures to enhance their stability and therapeutic effectiveness as antisense or aptamer oligomers. Some of them demonstrate various types of conjugation to driving ligands. The approved peptides comprise various structures, including linear, cyclic, and lipopeptides, and have diverse applications. Interestingly, the FDA has granted its first orphan drug designation for a peptide-based drug as a highly selective chemokine antagonist. Furthermore, Rett syndrome has found its first-ever core symptoms treatment, which is also peptide-based. Here, we analyze the TIDES approved in 2023 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects

Synthesis of New Peptide-Based Ligands with 1,2-HOPO Pendant Chelators and Thermodynamic Evaluation of Their Iron(III) Complexes**

Hydroxypyridones (HOPOs) are an important class of chelating compounds. They bind strongly to hard metal ions such as Fe(III). Here we present the solid-phase synthesis of peptides containing 1,2-HOPO moieties linked through a carboxylic acid placed at position 4 of the ring. A total of four ligands were studied, two bidentate and two hexadentate. The latter were synthesized by both stepwise and convergent strategies. The ligands and their complexes were characterized from the physico-chemical perspective. The pKa values for all ligands showed their total deprotonation at pH lower than the physiological pH. The formation constant of the Fe(III) complex (log β) ranged from 23.66, corresponding to ligand A, to 27.63, corresponding to ligand C. The pFe3+ at pH=7.4 revealed that ligands B and C had a strong iron affinity (26.91 and 28.58, respectively), thereby making them suitable for further study in therapeutic applications.The work was funded in part by the following: the National Research Foundation (NRF) (# 105892 and Blue Sky's Research Programme # 120386) and the University of KwaZulu-Natal (South Africa); and the Spanish Ministry of Science, Innovation, and Universities (RTI2018-093831-B-100), the Generalitat de Catalunya (2017 SGR 1439) (Spain), and Marató TV3 Foundation 2018 (#20183530). We thank Professor Miquel Viñas (University of Barcelona) for fruitful discussions.Peer reviewe