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Drug Discovery, Pharmaceutical Science, and Molecular Medicine

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.

0306 Physical Chemistry (incl. Structural), Methylene Chloride, green chemistry, General Chemistry, Sieber amide resin, Amides, 0305 Organic Chemistry, Peptide Fragments, peptide cleavage, protected peptide amide, 0302 Inorganic Chemistry, Amino Acids, Peptides, fragments condensation, and Resins, Plant

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.

Filtration and Separation and Analytical Chemistry

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.

Pharmacology, Structural Biology, Organic Chemistry, Drug Discovery, Molecular Medicine, General Medicine, Molecular Biology, and Biochemistry

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.

Aqueous media (ASPPS), Science & Technology, TETRAFLUOROBORATE, Chemistry, Multidisciplinary, Organic Chemistry, COUPLING REAGENTS, Pollution, RESIN, GREEN SOLVENTS, WATER-BASED SYNTHESIS, Chemistry, GAMMA-VALEROLACTONE GVL, N-PROTECTING GROUP, Physical Sciences, Environmental Chemistry, Science & Technology - Other Topics, AMINO-ACIDS, SUPPORTS, ACTIVE ESTERS, Peptides, Green & Sustainable Science & Technology, and 03 Chemical Sciences

Peptides have been gaining ground in the pharmaceutical arena, with a total of 22 approvals over the last six years. These molecules are also present in antibody-drug conjugate constructs as linkers or payloads, or both. Solid-phase peptide synthesis (SPPS) is the method of choice for peptide synthesis. The introduction of an automatic synthesizer facilitated this methodology and helped in reducing the amounts of the required solvents. However, there are still concerns regarding the amounts, as well as the safety profiles, of the solvents involved in SPPS. Here, we discuss the work addressing the use of water as the greenest alternative to the common non-green solvents employed in various steps of the SPPS methodology. Various technologies were introduced which enabled the synthesis of di- and up to decapeptides in aqueous media with satisfactory yields and purities.
The work in the author's laboratory is partially funded by the National Research Foundation (Blue Skies) (South Africa) and Al-Balqa Applied University, Jordan.

Oligonucleotides, Pharmaceutical Science, vosoritide, Inclisiran, drugs, antibody-drug conjugate, Dasiglucagon, Tisotumab vedotin-tftv, casimersen, Drug Discovery, voclosporin, tisotumab vedotin-tftv, pegcetacoplan, Pegcetacoplan, Antibody-drug conjugate, oligonucleotides, Casimersen, dasiglucagon, Drugs, Difelikefalin, difelikefalin, Voclosporin, Loncastuximab tesirine-lpyl, loncastuximab tesirine-lpyl, Piflufolastat-F18, odevixibat, peptides, Molecular Medicine, 1115 Pharmacology and Pharmaceutical Sciences, melphalan flufenamide, Peptides, inclisiran, FDA, Vosoritide, and Melphalan flufenamide

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.
The work performed by the authors is funded by the National Research Foundation (NRF) and the University of KwaZulu-Natal.

SELECTION, Research groups, Chemistry, Multidisciplinary, Cleavage (embryo), Chloride, chemistry.chemical_compound, Peptide synthesis, medicine, Environmental Chemistry, Organic chemistry, GAMMA-VALEROLACTONE, Green & Sustainable Science & Technology, Dichloromethane, Science & Technology, Organic Chemistry, 2-chlorotrityl chloride, Anisole, Pollution, GREEN SOLVENTS, Chemistry, chemistry, PRECIPITATION, Physical Sciences, ACID, Science & Technology - Other Topics, Hazardous solvents, 03 Chemical Sciences, Peptides, and medicine.drug

In recent years, the work of various research groups has allowed the substitution of the hazardous solvents most widely used in solid-phase peptide synthesis, namely DMF, NMP, DCM, DEE, among others, by several much less hazardous solvents. Indeed, greener alternatives have been found for almost all steps of the process, with the exception of the cleavage of protected peptides from 2-chlorotrityl chloride resin. Here, after careful screening of several of the so-called green solvents, we propose 2% TFA in either anisole or 1,3-dimethoxybenzene as optimal for the cleavage step. The higher boiling point of these solvents compared with the DCM allows the preparation of protected peptides with less risk of premature removal of the most labile protecting groups, such as the Trt of His. Our findings once again evidence the value/versatility of green solvents in strict chemical terms.
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) and the Generalitat de Catalunya (2017 SGR 1439) (Spain).

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).

Green chemistry, General Chemistry, Coupling reagent, Combinatorial chemistry, T3P ®, chemistry.chemical_compound, SPPS, chemistry, Phase (matter), Amidation, Peptide synthesis, 03 Chemical Sciences, and Peptides

Amidation is the predominant reaction within the pharmaceutical setting, and it is attracting greater attention due to the increased demand for therapeutic peptides. The high therapeutic efficacy and safety profile of peptides have placed these molecules in prime position within the pharmaceutical arena, which is reflected by these molecules receiving several approvals from various regulatory agencies each year. In this context, the demand for developing efficient strategies for peptide synthesis has also risen. Although propylphosphonic anhydride (T3P®), which has been recently proposed as a green coupling reagent, has shown good performance in solution, it has never been applied to solid-phase peptide synthesis (SPPS). Here we test the use of T3P® for SPPS. Satisfactory yields were achieved with a mild activation protocol. Various green solvents were tested and proved to be compatible with this coupling reagent. Several commonly used reagents cause allergic reactions or are susceptible to explosion under certain conditions. To overcome these issues, we propose T3P® as a potential alternative coupling reagent in SPPS.
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) and the Generalitat de Catalunya (2017 SGR 1439) (Spain).

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.