Lanthanide conjugates as versatile instruments for therapy and diagnostics

Lanthanides have demonstrated outstanding properties in many fields of research including biology and medicinal chemistry. Their unique luminescence and magnetic properties make them the metals of choice for next generation theranostics that efficiently combine the two central pillars of medicine – diagnostics and therapy. Attached to targeting units, lanthanide complexes pave the way for real-time imaging of drug uptake and distribution as well as specific regulation of subcellular processes with few side effects. This enables individualized treatment options for severe diseases characterized by altered cell expression. The highly diverse results achieved as well as insights into the challenges that research in this area has to face in the upcoming years will be summarized in the present review

Bio-instructive materials on-demand-combinatorial chemistry of peptoids, foldamers, and beyond

Combinatorial chemistry allows for the rapid synthesis of large compound libraries for high throughput screenings in biology, medicinal chemistry, or materials science. Especially compounds from a highly modular design are interesting for the proper investigation of structure-to-activity relationships. Permutations of building blocks result in many similar but unique compounds. The influence of certain structural features on the entire structure can then be monitored and serve as a starting point for the rational design of potent molecules for various applications. Peptoids, a highly diverse class of bioinspired oligomers, suit perfectly for combinatorial chemistry. Their straightforward synthesis on a solid support using repetitive reaction steps ensures easy handling and high throughput. Applying this modular approach, peptoids are readily accessible, and their interchangeable side-chains allow for various structures. Thus, peptoids can easily be tuned in their solubility, their spatial structure, and, consequently, their applicability in various fields of research. Since their discovery, peptoids have been applied as antimicrobial agents, artificial membranes, molecular transporters, and much more. Studying their three-dimensional structure, various foldamers with fascinating, unique properties were discovered. This non-comprehensive review will state the most interesting discoveries made over the past years and arouse curiosity about what may come

Cyclic Peptoid-Peptide Hybrids as Versatile Molecular Transporters

Addressing intracellular targets is a challenging task that requires potent molecular transporters capable to deliver various cargos. Herein, we report the synthesis of hydrophobic macrocycles composed of both amino acids and peptoid monomers. The cyclic tetramers and hexamers were assembled in a modular approach using solid as well as solution phase techniques. To monitor their intracellular localization, the macrocycles were attached to the fluorophore Rhodamine B. Most molecular transporters were efficiently internalized by HeLa cells and revealed a specific accumulation in mitochondria without the need for cationic charges. The data will serve as a starting point for the design of further cyclic peptoid-peptide hybrids presenting a new class of highly efficient, versatile molecular transporters

Synthesis of new pyrazolo[1,2,3]triazines by cyclative cleavage of pyrazolyltriazenes

We describe the synthesis of so far synthetically not accessible 3,6-substituted-4,6-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines as nitrogen-rich heterocycles. The target compounds were obtained in five steps, including an amidation and a cyclative cleavage reac-tion as key reaction steps. The introduction of two side chains allowed a variation of the pyrazolo[3,4-d][1,2,3]triazine core with commercially available building blocks, enabling the extension of the protocol to gain other derivatives straightforwardly. Attempts to synthesize 3,7-substituted-4,7-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines, the regioisomers of the successfully gained 3,6-substi-tuted 4,6-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines, were not successful under similar conditions due to the higher stability of the triazene functionality in the regioisomeric precursors and thus, the failure of the removal of the protective group.Peer reviewe

Structural Diversity of Peptoids: Tube-Like Structures of Macrocycles

Peptoids, or poly-N-substituted glycines, are characterised by broad structural diversity. Compared to peptides, they are less restricted in rotation and lack backbone-derived H bonding. Nevertheless, certain side chains force the peptoid backbone into distinct conformations. Designable secondary structures like helices or nanosheets arise from this knowledge. Herein, we report the copper-catalysed alkyne-azide cycloaddition (CuAAC) of macrocycles to form innovative tube-like tricyclic peptoids, giving access to host–guest chemistry or storage applications. Different linker systems make the single tubes tuneable in size and enable modifications within the gap. An azobenzene linker, which is reversibly switchable in conformation, was successfully incorporated and allowed for light-triggered changes of the entire tricyclic structure

Structural Diversity of Peptoids: Tube-Like Structures of Macrocycles

Peptoids, or poly-N-substituted glycines, are characterised by broad structural diversity. Compared to peptides, they are less restricted in rotation and lack backbone-derived H bonding. Nevertheless, certain side chains force the peptoid backbone into distinct conformations. Designable secondary structures like helices or nanosheets arise from this knowledge. Herein, we report the copper-catalysed alkyne-azide cycloaddition (CuAAC) of macrocycles to form innovative tube-like tricyclic peptoids, giving access to host–guest chemistry or storage applications. Different linker systems make the single tubes tuneable in size and enable modifications within the gap. An azobenzene linker, which is reversibly switchable in conformation, was successfully incorporated and allowed for light-triggered changes of the entire tricyclic structure

Macrocyclic tetramers—structural investigation of peptide-peptoid hybrids

Outstanding affinity and specificity are the main characteristics of peptides, rendering them interesting compounds for basic and medicinal research. However, their biological applicability is limited due to fast proteolytic degradation. The use of mimetic peptoids overcomes this disadvantage, though they lack stereochemical information at the α-carbon. Hybrids composed of amino acids and peptoid monomers combine the unique properties of both parent classes. Rigidification of the backbone increases the affinity towards various targets. However, only little is known about the spatial structure of such constrained hybrids. The determination of the three-dimensional structure is a key step for the identification of new targets as well as the rational design of bioactive compounds. Herein, we report the synthesis and the structural elucidation of novel tetrameric macrocycles. Measurements were taken in solid and solution states with the help of X-ray scattering and NMR spectroscopy. The investigations made will help to find diverse applications for this new, promising compound class

Macrocyclic Tetramers—Structural Investigation of Peptide-Peptoid Hybrids

Outstanding affinity and specificity are the main characteristics of peptides, rendering them interesting compounds for basic and medicinal research. However, their biological applicability is limited due to fast proteolytic degradation. The use of mimetic peptoids overcomes this disadvantage, though they lack stereochemical information at the α-carbon. Hybrids composed of amino acids and peptoid monomers combine the unique properties of both parent classes. Rigidification of the backbone increases the affinity towards various targets. However, only little is known about the spatial structure of such constrained hybrids. The determination of the three-dimensional structure is a key step for the identification of new targets as well as the rational design of bioactive compounds. Herein, we report the synthesis and the structural elucidation of novel tetrameric macrocycles. Measurements were taken in solid and solution states with the help of X-ray scattering and NMR spectroscopy. The investigations made will help to find diverse applications for this new, promising compound class

Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids

Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of antiviral drugs involves the identification of a unique viral target, followed by the design of an agent that addresses that target. Antimicrobial peptides (AMPs) represent a novel source of potential antiviral drugs. AMPs have been shown to inactivate numerous different enveloped viruses through the disruption of their viral envelopes. However, the clinical development of AMPs as antimicrobial therapeutics has been hampered by a number of factors, especially their enzymatically labile structure as peptides. We have examined the antiviral potential of peptoid mimics of AMPs (sequence-specific N-substituted glycine oligomers). These peptoids have the distinct advantage of being insensitive to proteases, and also exhibit increased bioavailability and stability. Our results demonstrate that several peptoids exhibit potent in vitro antiviral activity against both HSV-1 and SARS-CoV-2 when incubated prior to infection. In other words, they have a direct effect on the viral structure, which appears to render the viral particles non-infective. Visualization by cryo-EM shows viral envelope disruption similar to what has been observed with AMP activity against other viruses. Furthermore, we observed no cytotoxicity against primary cultures of oral epithelial cells. These results suggest a common or biomimetic mechanism, possibly due to the differences between the phospholipid head group makeup of viral envelopes and host cell membranes, thus underscoring the potential of this class of molecules as safe and effective broad-spectrum antiviral agents. We discuss how and why differing molecular features between 10 peptoid candidates may affect both antiviral activity and selectivity

Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids.

Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of antiviral drugs involves the identification of a unique viral target, followed by the design of an agent that addresses that target. Antimicrobial peptides (AMPs) represent a novel source of potential antiviral drugs. AMPs have been shown to inactivate numerous different enveloped viruses through the disruption of their viral envelopes. However, the clinical development of AMPs as antimicrobial therapeutics has been hampered by a number of factors, especially their enzymatically labile structure as peptides. We have examined the antiviral potential of peptoid mimics of AMPs (sequence-specific N-substituted glycine oligomers). These peptoids have the distinct advantage of being insensitive to proteases, and also exhibit increased bioavailability and stability. Our results demonstrate that several peptoids exhibit potent in vitro antiviral activity against both HSV-1 and SARS-CoV-2 when incubated prior to infection. In other words, they have a direct effect on the viral structure, which appears to render the viral particles non-infective. Visualization by cryo-EM shows viral envelope disruption similar to what has been observed with AMP activity against other viruses. Furthermore, we observed no cytotoxicity against primary cultures of oral epithelial cells. These results suggest a common or biomimetic mechanism, possibly due to the differences between the phospholipid head group makeup of viral envelopes and host cell membranes, thus underscoring the potential of this class of molecules as safe and effective broad-spectrum antiviral agents. We discuss how and why differing molecular features between 10 peptoid candidates may affect both antiviral activity and selectivity