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General Chemistry

The main strategies for the synthesis of Peptide Nucleic Acids (PNAs): key molecules as DNA/RNA mimics that can hybridize complementary chains of nucleic acids with high affinity and specificity.

chemistry.chemical_classification, Siderophore, Chelation, Peptide, General Chemistry, Combinatorial chemistry, chemistry, Protonation constants, Constants, Peptides, and Stability

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.

0301 basic medicine, 68Ga-PSMA-11, Ga-68-PSMA-11, Oligonucleotides, Pharmaceutical Science, lcsh:Medicine, lcsh:RS1-441, Chemistry, Medicinal, Review, International trade, belantamab mafodotin-blmf, drugs, 0302 clinical medicine, 64Cu-DOTATATE, Belantamab mafodotin-blmf, Viltolarsen, Drug Discovery, Pandemic, Global health, viltolarsen, Pharmacology & Pharmacy, media_common, oligonucleotides, setmelanotide, Setmelanotide, Authorization, lumasiran, 030220 oncology & carcinogenesis, Molecular Medicine, 1115 Pharmacology and Pharmaceutical Sciences, Life Sciences & Biomedicine, FDA, Drug, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), media_common.quotation_subject, Cu-64-DOTATATE, Food and drug administration, lcsh:Pharmacy and materia medica, 03 medical and health sciences, Science & Technology, business.industry, lcsh:R, 030104 developmental biology, peptides, Business, and Peptides

2020 has been an extremely difficult and challenging year as a result of the coronavirus disease 2019 (COVID-19) pandemic and one in which most efforts have been channeled into tackling the global health crisis. The US Food and Drug Administration (FDA) has approved 53 new drug entities, six of which fall in the peptides and oligonucleotides (TIDES) category. The number of authorizations for these kinds of drugs has been similar to that of previous years, thereby reflecting the consolidation of the TIDES market. Here, the TIDES approved in 2020 are analyzed in terms of chemical structure, medical target, mode of action, and adverse effects.
This work was funded in part by the following: the National Research Foundation (NRF) and the University of KwaZulu-Natal (South Africa); MINECO, (RTI2018-093831-B-100), and the Generalitat de Catalunya (2017 SGR 1439) (Spain).

Siderophore, 1-Hydroxypyridine-2-one, Carboxylic acid, Clinical Biochemistry, Siderophores, Peptide, 010501 environmental sciences, Cleavage (embryo), 01 natural sciences, Medicinal chemistry, 03 medical and health sciences, chemistry.chemical_compound, Solid-phase synthesis, Phase (matter), Moiety, Fe (III) chelators, lcsh:Science, 030304 developmental biology, 0105 earth and related environmental sciences, chemistry.chemical_classification, 0303 health sciences, Method Article, Solid phase peptide synthesis, Medical Laboratory Technology, chemistry, Benzyl group, lcsh:Q, and Trifluoromethanesulfonic acid (TFMSA)

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.

0301 basic medicine, Drug, DOTATOC, 68Ga-DOTATOC, givosiran, media_common.quotation_subject, Pharmaceutical market, Pharmaceutical Science, lcsh:Medicine, lcsh:RS1-441, Chemistry, Medicinal, ANTINEOPLASTIC AGENTS, Review, Pharmacology, golodirsen, polatuzumab vedotin, drugs, pharmaceutical market, 68ga dotatoc, lcsh:Pharmacy and materia medica, 03 medical and health sciences, HORMONE, 0302 clinical medicine, 68ga-dotatoc, Drug Discovery, MANAGEMENT, Medicine, Pharmacology & Pharmacy, media_common, enfortumab vedotin, Science & Technology, oligonucleotides, business.industry, lcsh:R, GA-68-DOTATOC, afamelanotide, DS-8201A, Polatuzumab vedotin, 030104 developmental biology, ADC, SAFETY, 030220 oncology & carcinogenesis, bremelanotide, peptides, Molecular Medicine, 1115 Pharmacology and Pharmaceutical Sciences, business, Life Sciences & Biomedicine, and ANTIBODY-DRUG CONJUGATE

2019 has been an excellent year in terms of peptides and oligonucleotides (TIDES) approved by the FDA. Despite the drop in the number of total drugs approved by the FDA in 2019 in comparison with 2018 (48 vs. 59), the total number of TIDES authorized increased (seven vs. three). Year after year, TIDES are increasingly present in therapy, as imaging agents, theragnostic and constituent moieties of other complex drugs, such as antibody drug conjugates. This means a consolidation of these kinds of drugs in the pharmaceutical arena, paving the way in the coming years for the approval of others for diverse medical indications. Here the TIDES approved in 2019 are analyzed in terms of chemical structure, medical target, mode of action, and adverse effects.

chemistry.chemical_classification, 010405 organic chemistry, Chemistry, Carboxylic acid, Organic Chemistry, Peptide, 010402 general chemistry, Ring (chemistry), Cleavage (embryo), 01 natural sciences, Biochemistry, Combinatorial chemistry, 0104 chemical sciences, chemistry.chemical_compound, Solid-phase synthesis, Drug Discovery, Benzyl group, Protecting group, and Derivative (chemistry)

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.

Siderophore, Microorganism, Iron, Medicinal & Biomolecular Chemistry, Trojan horse, Siderophores, medicine.disease_cause, Hydroxamic Acids, 01 natural sciences, Chemical synthesis, 0305 Organic Chemistry, Bacterial cell structure, Sideromycins, 03 medical and health sciences, Drug Discovery, Drug Resistance, Bacterial, medicine, Siderophore-drug conjugate, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, Bacteria, 0304 Medicinal and Biomolecular Chemistry, 010405 organic chemistry, Chemistry, Organic Chemistry, Pathogenic bacteria, General Medicine, biology.organism_classification, 0104 chemical sciences, Anti-Bacterial Agents, Fe (III) binding affinity, Biochemistry, Trojan, Hydroxamate, and 1115 Pharmacology and Pharmaceutical Sciences

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).
The work carried out in the laboratory 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 Marató TV3 foundation 2018 (#20183530). We thank Professor Miquel Viñas (University of Barcelona) for fruitful discussions.

patisiran, Pharmaceutical market, Pharmaceutical Science, lcsh:Medicine, lcsh:RS1-441, Chemistry, Medicinal, Review, Pharmacology, inotersen, drugs, pharmaceutical market, Food and drug administration, lcsh:Pharmacy and materia medica, Drug Discovery, Pharmacology & Pharmacy, Mode of action, Science & Technology, oligonucleotides, lcsh:R, dotatate, Onpattro, peptides, Molecular Medicine, Business, 1115 Pharmacology and Pharmaceutical Sciences, Lutathera, Tegsedi, and Life Sciences & Biomedicine

In 2018, the United States Food and Drug Administration (FDA) approved a total of 59 new drugs, three of them (5%) are TIDES (or also, -tides), two oligonucleotides and one peptide. Herein, the three TIDES approved are analyzed in terms of medical target, mode of action, chemical structure, and economics.

0301 basic medicine, PHARMACOKINETICS, HEMODIALYSIS, PLECANATIDE, ETELCALCETIDE, Pharmaceutical market, lcsh:Medicine, lcsh:RS1-441, Pharmaceutical Science, Chemistry, Medicinal, SERUM PARATHYROID-HORMONE, Peptide, Review, Pharmacology, 01 natural sciences, drugs, pharmaceutical market, AMG 416, lcsh:Pharmacy and materia medica, CALCIUM-SENSING RECEPTOR, general_medical_research, 03 medical and health sciences, Drug Discovery, Medicine, Pharmacology & Pharmacy, Mode of action, chemistry.chemical_classification, Science & Technology, Drug discovery, 010405 organic chemistry, business.industry, lcsh:R, SECONDARY HYPERPARATHYROIDISM, 0104 chemical sciences, AGONIST, 030104 developmental biology, chemistry, DISCOVERY, solid-phase peptide synthesis, Molecular Medicine, Plecanatide, 1115 Pharmacology and Pharmaceutical Sciences, business, and Life Sciences & Biomedicine

2017 was an excellent year in terms of new drugs (chemical entities and biologics) approved by the FDA, with a total of forty-six. In turn, one of the highlights was the number of peptides (six) included in this list. Here, the six peptides are analysed in terms of chemical structure, synthetic strategy used for their production, source, biological target, and mode of action.