Solid‐Phase Synthesis of Peptidomimetics with Peptide Backbone Modifications

Abdildinova, Aizhan; Kurth, Mark J.; Gong, Young‐Dae

doi:10.1002/ajoc.202100264

Cited by 16 publications

(18 citation statements)

References 144 publications

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“…Standard SPPS protocols have also been modified in order to adapt to the generation of peptidomimetic scaffolds. Accordingly, they were combined with click chemistry protocols, metal‐mediated reactions, N ‐alkylations, and N ‐acylations in order to incorporate diverse building blocks and functionalities [152] . As for traditional SPPS, one of the future development directions for the peptidomimetic solid‐phase synthesis will be the incorporation of green solvents and recyclable solid supports.…”

Section: Discussionmentioning

confidence: 99%

Amide Bonds Meet Flow Chemistry: A Journey into Methodologies and Sustainable Evolution

2022

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Formation of amide bonds is of immanent importance in organic and synthetic medicinal chemistry. Its presence in "traditional" small-molecule active pharmaceutical ingredients, in linear or cyclic oligo-and polypeptidic actives, including pseudopeptides, has led to the development of dedicated synthetic approaches for the formation of amide bonds starting from, if necessary, suitably protected amino acids. While the use of solid supported reagents is common in traditional peptide synthesis, similar approaches targeting amide bond formation in continuous-flow mode took off more significantly, after a first publication in 2006, only a couple of years ago. Most efforts rely upon the transition of traditional approaches in flow mode, or the combination of solid-phase peptide synthesis principles with flow chemistry, and advantages are mainly seen in improving space-time yields. This Review summarizes and compares the various approaches in terms of basic amide formation, peptide synthesis, and pseudopeptide generation, describing the technological approaches and the advantages that were generated by the specific flow approaches. A final discussion highlights potential future needs and perspectives in terms of greener and more sustainable syntheses.

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Section: Discussionmentioning

confidence: 99%

Amide Bonds Meet Flow Chemistry: A Journey into Methodologies and Sustainable Evolution

2022

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“…The development of newer synthetic strategies to obtain peptidomimetic drugs besides the evolution of solid-phase peptide synthesis (SPPS), , essential for mimetics with strong peptide character, has led to growing interest in this class of therapeutics, as evidenced by the list of drugs approved by the Food and Drug Administration (FDA) in the past few years ().…”

Section: Peptidomimetics Launched In the Market And Under Clinical Tr...mentioning

confidence: 99%

“…The development of newer synthetic strategies to obtain peptidomimetic drugs besides the evolution of solid-phase peptide synthesis (SPPS), 42,43 Recently, El-Faham et al 44 reported that 21 drugs of peptide and peptidomimetic nature were approved by FDA between January 2015 and May 2021 and represent 5% of all drugs launched into the market. Most of these new drugs exhibited a high degree of peptide character and do not really show a small molecule peptidomimetic nature, probably suggesting that peptides are more successful in drug development than peptidomimetics.…”

Section: Peptidomimetics Launched In the Market And Under Clinical Tr...mentioning

confidence: 99%

Peptidomimetics: An Overview of Recent Medicinal Chemistry Efforts toward the Discovery of Novel Small Molecule Inhibitors

2022

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The use of peptides as therapeutics has often been associated with several drawbacks such as poor absorption, low stability to proteolytic digestion, and fast clearance. Peptidomimetics are developed by modifications of native peptides with the aim of obtaining molecules that are more suitable for clinical development and, for this reason, are widely used as tools in medicinal chemistry programs. The effort to disclose innovative peptidomimetic therapies is recurrent and constantly evolving as demonstrated by the new lead compounds in clinical trials. Synthetic strategies for the development of peptidomimetics have also been implemented with time. This perspective highlights some of the most recent efforts for the design and synthesis of peptidomimetic agents together with their biological evaluation toward a panel of targets.

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“…The extraction of natural peptides can be expensive, but this problem is often overcome through solid phase peptide synthesis (SPPS) of the same or model peptides [ 72 ]. Sometimes, cytotoxicity, especially due to haemolytic activity, has been reported [ 28 , 73 ].…”

Section: Weak Points Of Ampsmentioning

confidence: 99%

Lights and Shadows on the Therapeutic Use of Antimicrobial Peptides

Bellotti

Remelli

2022

Molecules

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The emergence of antimicrobial-resistant infections is still a major concern for public health worldwide. The number of pathogenic microorganisms capable of resisting common therapeutic treatments are constantly increasing, highlighting the need of innovative and more effective drugs. This phenomenon is strictly connected to the rapid metabolism of microorganisms: due to the huge number of mutations that can occur in a relatively short time, a colony can “adapt” to the pharmacological treatment with the evolution of new resistant species. However, the shortage of available antimicrobial drugs in clinical use is also caused by the high costs involved in developing and marketing new drugs without an adequate guarantee of an economic return; therefore, the pharmaceutical companies have reduced their investments in this area. The use of antimicrobial peptides (AMPs) represents a promising strategy for the design of new therapeutic agents. AMPs act as immune defense mediators of the host organism and show a poor ability to induce antimicrobial resistance, coupled with other advantages such as a broad spectrum of activity, not excessive synthetic costs and low toxicity of both the peptide itself and its own metabolites. It is also important to underline that many antimicrobial peptides, due to their inclination to attack cell membranes, have additional biological activities, such as, for example, as anti-cancer drugs. Unfortunately, they usually undergo rapid degradation by proteolytic enzymes and are characterized by poor bioavailability, preventing their extensive clinical use and landing on the pharmaceutical market. This review is focused on the strength and weak points of antimicrobial peptides as therapeutic agents. We give an overview on the AMPs already employed in clinical practice, which are examples of successful strategies aimed at overcoming the main drawbacks of peptide-based drugs. The review deepens the most promising strategies to design modified antimicrobial peptides with higher proteolytic stability with the purpose of giving a comprehensive summary of the commonly employed approaches to evaluate and optimize the peptide potentialities.

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Solid‐Phase Synthesis of Peptidomimetics with Peptide Backbone Modifications

Cited by 16 publications

References 144 publications

Amide Bonds Meet Flow Chemistry: A Journey into Methodologies and Sustainable Evolution

Amide Bonds Meet Flow Chemistry: A Journey into Methodologies and Sustainable Evolution

Peptidomimetics: An Overview of Recent Medicinal Chemistry Efforts toward the Discovery of Novel Small Molecule Inhibitors

Lights and Shadows on the Therapeutic Use of Antimicrobial Peptides

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