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

Petri, Giovanna Li; Martino, Simona Di; Rosa, Maria de Lurdes Pereira

doi:10.1021/acs.jmedchem.2c00123

Cited by 47 publications

(34 citation statements)

References 123 publications

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“…Peptidomimetics are structural analogues of peptides that maintain structural elements and functionality of the native peptide but contain altered units or chemically distinct features. 89 In the context of 3°scaffold hopping, synthetic modifications derived from small molecules are introduced to a protein or peptide such as unnatural amino acid substitutions and secondary structure mimics (primarily turn mimetics). 89 In this discussion, this idea was used to distinguish 3°scaffold hopping from the myriad of other peptidomimetic strategies.…”

Section: "Cut Andmentioning

confidence: 99%

“…89 In the context of 3°scaffold hopping, synthetic modifications derived from small molecules are introduced to a protein or peptide such as unnatural amino acid substitutions and secondary structure mimics (primarily turn mimetics). 89 In this discussion, this idea was used to distinguish 3°scaffold hopping from the myriad of other peptidomimetic strategies. In each case, the role of 3°scaffold hopping has focused on maintaining biological activity while reducing peptide character and proteolytic susceptibility.…”

Section: "Cut Andmentioning

confidence: 99%

“…In this work, turn mimetics were introduced to replace various amino acid residues in the turn motif of Aβ 40 (highlighted in purple, 88, Figure 19). Replacements of this motif were made with unnatural turn mimetics such as bicyclic BTD (89) and aromatic TAA (90). 98 Two separate introductions of 89 as a replacement of either G 25 −S 26 or N 27 −K 28 caused no fibrillization of the protein, highlighting the importance of this feature for fibrillization.…”

Section: "Cut Andmentioning

confidence: 99%

“…The term peptidomimetic is used throughout literature to describe compounds with small changes (such as peptide bond replacements) to small molecules that elicit a similar biological response to an endogenous peptide. Peptidomimetics are structural analogues of peptides that maintain structural elements and functionality of the native peptide but contain altered units or chemically distinct features . In the context of 3° scaffold hopping, synthetic modifications derived from small molecules are introduced to a protein or peptide such as unnatural amino acid substitutions and secondary structure mimics (primarily turn mimetics) .…”

Section: Central Nervous System Drug Discoverymentioning

confidence: 99%

“…Figure19. Amino acid residues in the turn motif of Aβ 40(88) and turn replacements BTD(89) and TAA(90) 98. …”

mentioning

confidence: 99%

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Recent Scaffold Hopping Applications in Central Nervous System Drug Discovery

et al. 2022

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The concept of bioisosterism and the implementation of bioisosteric replacement is fundamental to medicinal chemistry. The exploration of bioisosteres is often used to probe key structural features of candidate pharmacophores and enhance pharmacokinetic properties. As the understanding of bioisosterism has evolved, capabilities to undertake more ambitious bioisosteric replacements have emerged. Scaffold hopping is a broadly used term in the literature referring to a variety of different bioisosteric replacement strategies, ranging from simple heterocyclic replacements to topological structural overhauls. In this work, we have highlighted recent applications of scaffold hopping in the central nervous system drug discovery space. While we have highlighted the benefits of using scaffold hopping approaches in central nervous system drug discovery, these are also widely applicable to other medicinal chemistry fields. We also recommend a shift toward the use of more refined and meaningful terminology within the realm of scaffold hopping.

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Section: "Cut Andmentioning

confidence: 99%

Section: "Cut Andmentioning

confidence: 99%

Section: "Cut Andmentioning

confidence: 99%

Section: Central Nervous System Drug Discoverymentioning

confidence: 99%

“…Figure19. Amino acid residues in the turn motif of Aβ 40(88) and turn replacements BTD(89) and TAA(90) 98. …”

mentioning

confidence: 99%

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Recent Scaffold Hopping Applications in Central Nervous System Drug Discovery

et al. 2022

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Opine dehydrogenases, an underexplored enzyme family for the enzymatic synthesis of chiral amines

Telek

Molnár

Vértessy

et al. 2023

Biotech & Bioengineering

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Opines and opine‐type chemicals are valuable natural products with diverse biochemical roles, and potential synthetic building blocks of bioactive compounds. Their synthesis involves reductive amination of ketoacids with amino acids. This transformation has high synthetic potential in producing enantiopure secondary amines. Nature has evolved opine dehydrogenases for this chemistry. To date, only one enzyme has been used as biocatalyst, however, analysis of the available sequence space suggests more enzymes to be exploited in synthetic organic chemistry. This review summarizes the current knowledge of this underexplored enzyme class, highlights key molecular, structural, and catalytic features with the aim to provide a comprehensive general description of opine dehydrogenases, thereby supporting future enzyme discovery and protein engineering studies.

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Isocyanide–Based Multicomponent Reactions Coupled One–Pot Process: Efficient Tools to Diversity–Oriented Synthesis of Structural Peptidomimetics

Kaveti,

Rentería‐Gómez,

Corona‐Díaz

et al. 2024

ChemPlusChem

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Multicomponent diversity‐oriented synthesis (DOS) of conformationally anchored structural peptidomimetics like 2,5‐diketopiperazines (2,5‐DKP) containing heterocyclic bioisosteres of the amide bond, such as 1,2,3‐triazoles and 1,5‐disubstituted tetrazoles (1,5‐DS‐T) is described. Structural peptidomimetics are synthesized from similar available starting materials, via a strategy based on isocyanide‐based multicomponent reactions (IMCRs): Ugi‐4CR and Ugi‐Azide (UA), followed by a one‐pot process: SN2/intramolecular alkyne‐azide cycloaddition (IAAC). The sequential aligning of two powerful synthetic tools (IMCR and IAAC) has parallelly contributed to generate anchored conformation and complexity in target molecules, which are considered structural peptidomimetics of 2,5‐DKP. Herein, the 1,2,3‐triazole ring plays a key role in the preference for the boat conformation. Furthermore, the use of different IMCRs generates scaffold diversity at the N‐1 α‐carbon of the pyrazinone ring, replacing a linear amide bond with a heterocyclic bioisostere like 1,5‐DS‐T leading to the synthesis of novel tricyclic peptidomimetics. The DFT calculations confirmed the boat conformation of the synthesized molecules.

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

Cited by 47 publications

References 123 publications

Recent Scaffold Hopping Applications in Central Nervous System Drug Discovery

Recent Scaffold Hopping Applications in Central Nervous System Drug Discovery

Opine dehydrogenases, an underexplored enzyme family for the enzymatic synthesis of chiral amines

Isocyanide–Based Multicomponent Reactions Coupled One–Pot Process: Efficient Tools to Diversity–Oriented Synthesis of Structural Peptidomimetics

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