Peptide-based drug discovery: Current status and recent advances

Drug Discovery Today, Год журнала: 2022, Номер 28(2), С. 103464 - 103464

Опубликована: Дек. 5, 2022

Язык: Английский

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Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Organic Process Research & Development, Год журнала: 2022, Номер 26(6), С. 1562 - 1689

Опубликована: Июнь 7, 2022

This review describes the practical aspects involved in implementation of large-scale amidations process chemistry. Coupling reagent, base, additive, and solvent selections are critically analyzed to highlight their pros cons. Other important factors be considered on large scale, such as atom economy, cost, safety, toxicity, also examined. These concepts then showcased through selected examples from literature for synthesis active pharmaceutical ingredients.

Язык: Английский

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Process Mass Intensity (PMI): A Holistic Analysis of Current Peptide Manufacturing Processes Informs Sustainability in Peptide Synthesis

The Journal of Organic Chemistry, Год журнала: 2024, Номер 89(7), С. 4261 - 4282

Опубликована: Март 20, 2024

Small molecule therapeutics represent the majority of FDA-approved drugs. Yet, many attractive targets are poorly tractable by small molecules, generating a need for new therapeutic modalities. Due to their biocompatibility profile and structural versatility, peptide-based possible solution. Additionally, in past two decades, advances peptide design, delivery, formulation, devices have occurred, making peptides an modality. However, manufacturing is often limited solid-phase synthesis (SPPS), liquid phase (LPPS), lesser extent hybrid SPPS/LPPS, with SPPS emerging as predominant platform technology synthesis. involves use excess solvents reagents which negatively impact environment, thus highlighting newer technologies reduce environmental footprint. Herein, fourteen American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR) member companies portfolio compiled Process Mass Intensity (PMI) metrics help inform sustainability efforts This includes PMI assessment on 40 synthetic processes at various development stages pharma, classified according phase. most comprehensive date. The process was divided into (synthesis, purification, isolation) determine respective PMI. On average, (SPPS) (PMI ≈ 13,000) does not compare favorably other modalities such molecules median 168–308) biopharmaceuticals 8300). Thus, high warrants more environmentally friendly manufacturing.

Язык: Английский

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Recent developments in catalytic amide bond formation

Peptide Science, Год журнала: 2020, Номер 112(6)

Опубликована: Ноя. 1, 2020

Abstract Amide bond forming reactions are critical for both polypeptide synthesis and medicinal chemistry. Most current approaches amidation employ stoichiometric activating agents, but such methods neither atom economical nor synthetically elegant. Catalytic potentially green more ideal substitutes standard thus the subject of this review. Such face significant thermodynamic kinetic barriers have, as a result, historically conceded use elevated temperatures dehydrating agents or lacked broad relevant substrate scopes from perspective peptide Recent advancements in direct (the coupling carboxylic acid an amine) indirect other partners resulting amide bond) based on aryl boronic acids, transition metals organocatalysis former ester redox‐coupled later, address these previous shortcomings examined therein.

Язык: Английский

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Active ester-based peptide bond formation and its application in peptide synthesis

Organic Chemistry Frontiers, Год журнала: 2023, Номер 10(7), С. 1817 - 1846

Опубликована: Янв. 1, 2023

Active ester method is an efficient strategy to address the notorious racemization/epimerization issue of peptide bond formation. Herein, pros and cons using active esters for synthesis were systematically summarized analyzed.

Язык: Английский

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Rational Design of an Organocatalyst for Peptide Bond Formation

Journal of the American Chemical Society, Год журнала: 2019, Номер 141(40), С. 15977 - 15985

Опубликована: Сен. 11, 2019

Amide bonds are ubiquitous in peptides, proteins, pharmaceuticals, and polymers. The formation of amide is a straightforward process: can be synthesized with relative ease because the availability efficient coupling agents. However, there substantive need for methods that do not require excess reagents. A catalyst condenses amino acids could have an important impact by reducing significant waste generated during peptide synthesis. We describe rational design biomimetic efficiently couple featuring standard protecting groups. combines lessons learned from enzymes, biosynthesis, organocatalysts. Under optimized conditions, 5 mol % couples Fmoc without notable racemization. Importantly, we demonstrate functional synthesis oligopeptides on solid phase. This result it illustrates potential to function substrate multitude bonds, which may expected inhibit hydrogen-bonding catalyst.

Язык: Английский

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Catalytic Dehydrative Peptide Synthesis with gem-Diboronic Acids

ACS Catalysis, Год журнала: 2019, Номер 10(1), С. 683 - 688

Опубликована: Дек. 12, 2019

Alkane-gem-diboronic acids have emerged as versatile organoboron catalysts for dehydrative amidation of α-amino acids. A phenol-substituted multiboron catalyst with a B–C–B structure outperformed simple arylboronic in the condensation suppressed epimerization electrophiles. gem-diboronic acid catalysis were compatible various O, N, and S-functionalized bearing N-protecting groups including common carbamates used peptide synthesis (Boc, Cbz, Fmoc). N-trifluoroacetyl protection enabled an unprecedented catalytic at room temperature. Preliminary mechanistic studies revealed carboxylate-binding nature acids, orthogonal to activation carboxylic by The distinctive reactivity would open prospects mild condensation.

Язык: Английский

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Peptide Bond-Forming Reaction via Amino Acid Silyl Esters: New Catalytic Reactivity of an Aminosilane

ACS Catalysis, Год журнала: 2020, Номер 10(16), С. 9594 - 9603

Опубликована: Июль 31, 2020

The epimerization-free formation of peptide bonds is crucial for the development therapeutics and pharmaceuticals. Herein, we report a hydrosilane-mediated approach construction between most amino acids under ambient conditions. This concise protocol with an original silylating reagent HSi(OCH(CF3)2)3 facilitates use bearing broad variety functional groups without any epimerization. Moreover, catalytic system using aminosilane catalyst enables not only acceleration in silylation carboxylic but also amide synthesis minimal substrate (electrophile/nucleophile/silylating = 1:1:1) waste production (hydrogen gas siloxane). These simple powerful approaches are established as potentially general paradigm desired peptides high yields.

Язык: Английский

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Allenone-Mediated Racemization/Epimerization-Free Peptide Bond Formation and Its Application in Peptide Synthesis

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(27), С. 10374 - 10381

Опубликована: Июнь 30, 2021

Allenone has been identified as a highly effective peptide coupling reagent for the first time. The bond was formed with an α-carbonyl vinyl ester key intermediate, formation and subsequent aminolysis of which proceed spontaneously in racemization-/epimerization-free manner. allenone not only is synthesis simple amides dipeptides but also amenable to fragment condensation solid-phase (SPPS). robustness allenone-mediated showcased incisively by carfilzomib, involved rare N C elongation strategy. Furthermore, successful model difficult ACP (65-74) on solid support suggested that this method compatible SPPS. This combines advantages conventional active esters reagents, while overcoming disadvantages both strategies. Thus, strategy represents disruptive innovation synthesis.

Язык: Английский

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Manganese Catalyzed Direct Amidation of Esters with Amines

The Journal of Organic Chemistry, Год журнала: 2021, Номер 86(3), С. 2339 - 2358

Опубликована: Янв. 7, 2021

The transition metal catalyzed amide bond forming reaction of esters with amines has been developed as an advanced approach for overcoming the shortcomings traditional methods. broad scope substrates in amidations remains a challenge. Here, manganese(I)-catalyzed method direct synthesis amides from various number and is reported unprecedented substrate using low catalyst loading. A wide range aromatic, aliphatic, heterocyclic esters, even fatty acid reacted diverse primary aryl amines, alkyl secondary to form amides. It noteworthy that this provides first example amines. acid–base mechanism amidation was elucidated by DFT calculations.

Язык: Английский

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