Exploring FDA-Approved Frontiers: Insights into Natural and Engineered Peptide Analogues in the GLP-1, GIP, GHRH, CCK, ACTH, and α-MSH Realms

Peptides continue to gain significance in the pharmaceutical arena. Since the unveiling of insulin in 1921, the Food and Drug Administration (FDA) has authorised around 100 peptides for various applications. Peptides, although initially derived from endogenous sources, have evolved beyond their natural origins, exhibiting favourable therapeutic effectiveness. Medicinal chemistry has played a pivotal role in synthesising valuable natural peptide analogues, providing synthetic alternatives with therapeutic potential. Furthermore, key chemical modifications have enhanced the stability of peptides and strengthened their interactions with therapeutic targets. For instance, selective modifications have extended their half-life and lessened the frequency of their administration while maintaining the desired therapeutic action. In this review, I analyse the FDA approval of natural peptides, as well as engineered peptides for diabetes treatment, growth-hormone-releasing hormone (GHRH), cholecystokinin (CCK), adrenocorticotropic hormone (ACTH), and α-melanocyte stimulating hormone (α-MSH) peptide analogues. Attention will be paid to the structure, mode of action, developmental journey, FDA authorisation, and the adverse effects of these peptides

Peptide Therapeutics: Unveiling the Potential against Cancer—A Journey through 1989

The United States Food and Drug Administration (FDA) has approved a plethora of peptide-based drugs as effective drugs in cancer therapy. Peptides possess high specificity, permeability, target engagement, and a tolerable safety profile. They exhibit selective binding with cell surface receptors and proteins, functioning as agonists or antagonists. They also serve as imaging agents for diagnostic applications or can serve a dual-purpose as both diagnostic and therapeutic (theragnostic) agents. Therefore, they have been exploited in various forms, including linkers, peptide conjugates, and payloads. In this review, the FDA-approved prostate-specific membrane antigen (PSMA) peptide antagonists, peptide receptor radionuclide therapy (PRRT), somatostatin analogs, antibody–drug conjugates (ADCs), gonadotropin-releasing hormone (GnRH) analogs, and other peptide-based anticancer drugs are analyzed in terms of their chemical structures and properties, therapeutic targets and mechanisms of action, development journey, administration routes, and side effects

Greener cleavage of protected peptide fragments from Sieber Amide Resin.

Following the successful introduction of two benign solvents for cleaving protected acid peptide fragments from 2-chlorotrityl chloride (2-CTC) resin, there is a need to green the cleavage process for obtaining protected peptide amide fragments. In this work, p-xylene and toluene are introduced as greener alternates to dichloromethane (DCM) for preparing protected peptide amide fragments from a Sieber amide resin. The N-dealkylation is a demanding chemical reaction, requiring that the cleavage protocol be optimised to ensure complete cleavage from the resin. After a 30 min reaction time, only 66 % of the final peptide product was retrieved even with the conventional dichloromethane solvent. Therefore, 120 min was considered sufficient to fully cleave the peptide from the Sieber amide resin. This work reaffirms the fact that greening strategies are far from detrimental, with green alternatives often outperforming their replaced counterparts

Photocatalytic Degradation of Antibiotics via Exploitation of a Magnetic Nanocomposite: A Green Nanotechnology Approach toward Drug-Contaminated Wastewater Reclamation

In the quest for eco-conscious innovations, this research was designed for the sustainable synthesis of magnetite (Fe3O4) nanoparticles, using ferric chloride hexahydrate salt as a precursor and extract of Eucalyptus globulus leaves as both a reducing and capping agent, which are innovatively applied as a photocatalyst for the photocatalytic degradation of antibiotics “ciprofloxacin and amoxicillin”. Sugar cane bagasse biomass, sugar cane bagasse pyrolyzed biochar, and magnetite/sugar cane bagasse biochar nanocomposite were also synthesized via environmentally friendly organized approaches. The optimum conditions for the degradation of ciprofloxacin and amoxicillin were found to be pH 6 for ciprofloxacin and 5 for amoxicillin, dosage of the photocatalyst (0.12 g), concentration (100 mg/L), and irradiation time (240 min). The maximum efficiencies of percentage degradation for ciprofloxacin and amoxicillin were found to be (73.51%) > (63.73%) > (54.57%) and (74.07%) > (61.55%) > (50.66%) for magnetic nanocomposites, biochar, and magnetic nanoparticles, respectively. All catalysts demonstrated favorable performance; however, the “magnetite/SCB biochar” nanocomposite exhibited the most promising results among the various catalysts employed in the photocatalytic degradation of antibiotics. Kinetic studies for the degradation of antibiotics were also performed, and notably, the pseudo-first-order chemical reaction showed the best results for the degradation of antibiotics. Through a comprehensive and comparative analysis of three unique photocatalysts, this research identified optimal conditions for efficient treatment of drug-contaminated wastewater, thus amplifying the practical significance of the findings. The recycling of magnetic nanoparticles through magnetic separation, coupled with their functional modification for integration into composite materials, holds significant application potential in the degradation of antibiotics

Greener Cleavage of Protected Peptide Fragments from Sieber Amide Resin

Following the successful introduction of two benign solvents for cleaving protected acid peptide fragments from 2-chlorotrityl chloride (2-CTC) resin, there is a need to green the cleavage process for obtaining protected peptide amide fragments. In this work, p-xylene and toluene are introduced as greener alternates to dichloromethane (DCM) for preparing protected peptide amide fragments from a Sieber amide resin. The N-dealkylation is a demanding chemical reaction, requiring that the cleavage protocol be optimised to ensure complete cleavage from the resin. After a 30 min reaction time, only 66 % of the final peptide product was retrieved even with the conventional dichloromethane solvent. Therefore, 120 min was considered sufficient to fully cleave the peptide from the Sieber amide resin. This work reaffirms the fact that greening strategies are far from detrimental, with green alternatives often outperforming their replaced counterparts

2023 FDA TIDES (Peptides and Oligonucleotides) Harvest

A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The approved four oligonucleotide 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 showed 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, lipopeptides and with diverse applications. Interestingly, the FDA has granted an orphan drug designation for a first 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 one. Here we analyse the TIDES approved in 2023 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects

Prediction of peptides retention behavior in reversed-phase liquid chromatography based on their hydrophobicity

Hydrophobicity is an important physicochemical property of peptides and proteins. It is responsible for their conformational changes, stability, as well as various chemical intramolecular and intermolecular interactions. Enormous efforts have been invested to study the extent of hydrophobicity and how it could influence various biological processes, in addition to its crucial role in the separation and purification endeavor as well. Here, we have reviewed various studies that were carried out to determine the hydrophobicity starting from (i) simple amino acids solubility behavior, (ii) experimental approach that was undertaken in the reversed-phase liquid chromatography mode, and ending with (iii) some examples of more advanced computational and machine learning models

Successful synthesis of a glial-specific blood-brain barrier shuttle peptide following a fragment condensation approach on a solid-phase resin

Successful manual synthesis of the TD2.2 peptide acting as a blood-brain barrier shuttle was achieved. TD2.2 was successfully synthesised by sequential condensation of four protected peptide fragments on solid-phase settings, after several unsuccessful attempts using the stepwise approach. These fragments were chosen to minimize the number of demanding amino acids (in terms of coupling, Fmoc removal) in each fragment that are expected to hamper the overall synthetic process. Thus, the hydrophobic amino acids as well as Fmoc-Arg (Pbf)-OH were strategically spread over multiple fragments rather than having them congested in one fragment. This study shows how a peptide that shows big challenges in the synthesis using the common stepwise elongation methodology can be synthesised with an acceptable purity. It also emphasises that choosing the right fragment with certain amino acid constituents is key for a successful synthesis. It is worth highlighting that lower amounts of reagents were required to synthesise the final peptide with an identical purity to that obtained by the automatic synthesiser