Factors influencing the prediction accuracy of model peptides in reversed-phase liquid chromatography

Hydrophobicity is an important physicochemical property of peptides in solution. As well as being strongly associated with peptide stability and aggregation, hydrophobicity governs the solution based chromatographic separation processes, specifically reversed-phase liquid chromatography (RPLC). In addition, hydrophobicity is a major physicochemical property of peptides in comparison to H-bonding, electrostatic, and aromatic properties in intermolecular interactions. However, a wide range of molecular factors can influence peptide hydrophobicity, with accurate predictions depending on specific peptide amino acid compositions, structure, and conformation. It is noticeable that peptide composition, the position of the amino acid, and its neighbouring groups play a crucial role in the elution process. In light of this, the same amino acid behaved differently depending on its position and neighbouring amino acid in the peptide chain. Extra attention should be paid to the denaturation process during the course of elution, as it has been shown to complicate and alter the elution pattern. This paper reports on the key peptide properties that can alter hydrophobicity and, consequently, the RPLC elution behaviour of the peptides, and it will conclude by proposing improved prediction algorithms for peptide elution in RPLC

Strategies for improving peptide stability and delivery

Peptides play an important role in many fields, including immunology, medical diagnostics, and drug discovery, due to their high specificity and positive safety profile. However, for their delivery as active pharmaceutical ingredients, delivery vectors, or diagnostic imaging molecules, they suffer from two serious shortcomings: their poor metabolic stability and short half-life. Major research efforts are being invested to tackle those drawbacks, where structural modifications and novel delivery tactics have been developed to boost their ability to reach their targets as fully functional species. The benefit of selected technologies for enhancing the resistance of peptides against enzymatic degradation pathways and maximizing their therapeutic impact are also reviewed. Special note of cell-penetrating peptides as delivery vectors, as well as stapled modified peptides, which have demonstrated superior stability from their parent peptides, are reported

Determining the hydrophobicity index of protected amino acids and common protecting groups

Peptides are in great demand in the pharmaceutical arena and a majority of these peptides contain 20 or more amino acids. They are infrequently synthesised using the fragment condensation approach. A key limitation in adopting this approach more commonly is that protected peptide fragments with high purity are often required prior to the final condensation steps. It is hypothesized that understanding the hydrophobic nature of the protected amino acids will assist with designing optimal fragment purification processes when needed. Whilst a myriad of hydrophobicity indices are reported in the literature for unprotected amino acids, the literature lacks any data regarding the protected amino acids which form the key precursor for the fragment condensation task. In this current study, hydrophobicity indices for protected amino acids with common α-amino and sidechain protecting groups were experimentally determined. Different positions for each amino acid within the peptide chain were considered, namely at the C-terminal and N-terminal as well as internal positions. These data give deep insights on the hydrophobicity of each amino acid with respect to its position in the peptide chain. The data acquired in this research facilitated the prediction of the retention time of protected peptide fragments with an uncertainty of less than ±1.5%

2022 FDA TIDES (peptides and oligonucleotides) harvest

A total of 37 new drug entities were approved in 2022; although that year registered the lowest number of drug approvals since 2016, the TIDES class consolidated its presence with a total of five authorizations (four peptides and one oligonucleotide). Interestingly, 23 out of 37 drugs were first-in-class and thus received fast-track designation by the FDA in categories such as breakthrough therapy, priority review voucher, orphan drug, accelerated approval, and so on. Here, we analyze the TIDES approved in 2022 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects

2021 FDA TIDES (peptides and oligonucleotides) harvest

From the medical, pharmaceutical, and social perspectives, 2021 has been a year dominated by the COVID-19 pandemic. However, despite this global health crisis, the pharmaceutical industry has continued its endeavors, and 2021 could be considered an excellent year in terms of the drugs accepted by the US Food and Drug Administration (FDA). Thus, during this year, the FDA has approved 50 novel drugs, of which 36 are new chemical entities and 14 biologics. It has also authorized 10 TIDES (8 peptides, 2 oligonucleotides), in addition to 2 antibody-drug conjugates (ADCs) whose structures contain peptides. Thus, TIDES have accounted for about 24% of the approvals in the various drug categories. Importantly, this percentage has surpassed the figure in 2020 (10%), thus reflecting the remarkable success of TIDES. In this review, the approved TIDE-based drugs are analyzed on the basis of their chemical structure, medical target, mode of action, administration route, and adverse effects

Calculating resin functionalization in solid-phase peptide synthesis using a standardized method based on Fmoc determination

Solid-phase synthesis is the method of choice for peptide preparation in both research and industrial settings. The whole synthetic process is governed by the initial functionalization of the resin. Although the literature provides several methods to determine such functionalization, the addition of an Fmoc-amino acid and the posterior spectrophotometric measurement of the dibenzofulvene adduct formed after Fmoc removal is the most widely used for this purpose. However, a range of molar extinction coefficient (ε) values and even wavelengths are currently used in the field, with no standardization of the method. Here, we propose a single-point standardization method that involves a standard solution of the corresponding amino acid to be checked that is prepared freshly at the time of the analysis

Hydroxamate siderophores: natural occurrence, chemical synthesis, iron binding affinity and use as Trojan horses against pathogens.

Hydroxamic acids are an important class of molecules, in particular because of their metal-chelating ability. Microorganisms, including pathogenic bacteria, use hydroxamate-based entities (siderophores), among others, to acquire Fe (III). The "Trojan horse" strategy exploits the need of bacteria for this metal by using Fe (III) active transporters to carry antibacterial or bactericidal moieties into the bacterial cell. Many natural Trojan horses (sideromycins) are derived from hydroxamic acids, thereby reflecting their potency. Various artificial sideromycins and their antibacterial activities have been reported. This review discusses the structural aspects of the hydroxamate-siderophores isolated in the last two decades, the chemical synthesis of their building blocks, their binding affinity towards Fe (III), and their application as Trojan horses (weaknesses and strengths)