scholarly journals Modulating Protein–Protein Interactions by Cyclic and Macrocyclic Peptides. Prominent Strategies and Examples

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 445
Author(s):  
Rosario González-Muñiz ◽  
María Ángeles Bonache ◽  
María Jesús Pérez de Vega

Cyclic and macrocyclic peptides constitute advanced molecules for modulating protein–protein interactions (PPIs). Although still peptide derivatives, they are metabolically more stable than linear counterparts, and should have a lower degree of flexibility, with more defined secondary structure conformations that can be adapted to imitate protein interfaces. In this review, we analyze recent progress on the main methods to access cyclic/macrocyclic peptide derivatives, with emphasis in a few selected examples designed to interfere within PPIs. These types of peptides can be from natural origin, or prepared by biochemical or synthetic methodologies, and their design could be aided by computational approaches. Some advances to facilitate the permeability of these quite big molecules by conjugation with cell penetrating peptides, and the incorporation of β-amino acid and peptoid structures to improve metabolic stability, are also commented. It is predicted that this field of research could have an important future mission, running in parallel to the discovery of new, relevant PPIs involved in pathological processes.

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Charlotte Rimbault ◽  
Kashyap Maruthi ◽  
Christelle Breillat ◽  
Camille Genuer ◽  
Sara Crespillo ◽  
...  

Abstract Designing highly specific modulators of protein-protein interactions (PPIs) is especially challenging in the context of multiple paralogs and conserved interaction surfaces. In this case, direct generation of selective and competitive inhibitors is hindered by high similarity within the evolutionary-related protein interfaces. We report here a strategy that uses a semi-rational approach to separate the modulator design into two functional parts. We first achieve specificity toward a region outside of the interface by using phage display selection coupled with molecular and cellular validation. Highly selective competition is then generated by appending the more degenerate interaction peptide to contact the target interface. We apply this approach to specifically bind a single PDZ domain within the postsynaptic protein PSD-95 over highly similar PDZ domains in PSD-93, SAP-97 and SAP-102. Our work provides a paralog-selective and domain specific inhibitor of PSD-95, and describes a method to efficiently target other conserved PPI modules.


2017 ◽  
Vol 60 (21) ◽  
pp. 8982-8988 ◽  
Author(s):  
Dennis M. Krüger ◽  
Adrian Glas ◽  
David Bier ◽  
Nicole Pospiech ◽  
Kerstin Wallraven ◽  
...  

Reproduction ◽  
2004 ◽  
Vol 127 (4) ◽  
pp. 423-429 ◽  
Author(s):  
Keisuke Kaji ◽  
Akira Kudo

Sperm–oocyte fusion is one of the most impressive events in sexual reproduction, and the elucidation of its molecular mechanism has fascinated researchers for a long time. Because of the limitation of materials and difficulties in analyzing membrane protein–protein interactions, many attempts have failed to reach this goal. Recent studies involving gene targeting have clearly demonstrated the various molecules that are involved in sperm–oocyte binding and fusion. Sperm ADAMs (family of proteins with a disintegrin and metalloprotease domain), including fertilin α, fertilin β and cyritestin, have been investigated and found to be important for binding rather than for fusion and painstaking studies have raised suspicions that their putative receptors, oocyte integrins, are necessary for the sperm–oocyte interaction. Recently, several studies have focused the spotlight on CD9 and glycosylphosphatidylinositol (GPI)-anchored proteins on oocytes, and epididymal protein DE on sperm, as candidate molecules involved in sperm–oocyte fusion. Lack of, or interference with the function of, these proteins can disrupt the sperm–oocyte fusion without changing the binding. In this review we highlight the candidate molecules involved in the sperm–oocyte interaction suggested from the recent progress in this research field.


2016 ◽  
Vol 113 (52) ◽  
pp. 15018-15023 ◽  
Author(s):  
Juan Rodriguez-Rivas ◽  
Simone Marsili ◽  
David Juan ◽  
Alfonso Valencia

Protein–protein interactions are fundamental for the proper functioning of the cell. As a result, protein interaction surfaces are subject to strong evolutionary constraints. Recent developments have shown that residue coevolution provides accurate predictions of heterodimeric protein interfaces from sequence information. So far these approaches have been limited to the analysis of families of prokaryotic complexes for which large multiple sequence alignments of homologous sequences can be compiled. We explore the hypothesis that coevolution points to structurally conserved contacts at protein–protein interfaces, which can be reliably projected to homologous complexes with distantly related sequences. We introduce a domain-centered protocol to study the interplay between residue coevolution and structural conservation of protein–protein interfaces. We show that sequence-based coevolutionary analysis systematically identifies residue contacts at prokaryotic interfaces that are structurally conserved at the interface of their eukaryotic counterparts. In turn, this allows the prediction of conserved contacts at eukaryotic protein–protein interfaces with high confidence using solely mutational patterns extracted from prokaryotic genomes. Even in the context of high divergence in sequence (the twilight zone), where standard homology modeling of protein complexes is unreliable, our approach provides sequence-based accurate information about specific details of protein interactions at the residue level. Selected examples of the application of prokaryotic coevolutionary analysis to the prediction of eukaryotic interfaces further illustrate the potential of this approach.


2021 ◽  
Author(s):  
Shuhui Lim ◽  
Nicolas Boyer ◽  
Nicole Boo ◽  
Chunhui Huang ◽  
Gireedhar Venkatachalam ◽  
...  

Macrocyclic peptides have the potential to address intracellular protein-protein interactions (PPIs) of high value therapeutic targets that have proven largely intractable to small molecules. Here, we report broadly applicable lessons...


2019 ◽  
Vol 20 (7) ◽  
pp. 1583 ◽  
Author(s):  
Dàmaris Navío ◽  
Mireia Rosell ◽  
Josu Aguirre ◽  
Xavier de la Cruz ◽  
Juan Fernández-Recio

One of the known potential effects of disease-causing amino acid substitutions in proteins is to modulate protein-protein interactions (PPIs). To interpret such variants at the molecular level and to obtain useful information for prediction purposes, it is important to determine whether they are located at protein-protein interfaces, which are composed of two main regions, core and rim, with different evolutionary conservation and physicochemical properties. Here we have performed a structural, energetics and computational analysis of interactions between proteins hosting mutations related to diseases detected in newborn screening. Interface residues were classified as core or rim, showing that the core residues contribute the most to the binding free energy of the PPI. Disease-causing variants are more likely to occur at the interface core region rather than at the interface rim (p < 0.0001). In contrast, neutral variants are more often found at the interface rim or at the non-interacting surface rather than at the interface core region. We also found that arginine, tryptophan, and tyrosine are over-represented among mutated residues leading to disease. These results can enhance our understanding of disease at molecular level and thus contribute towards personalized medicine by helping clinicians to provide adequate diagnosis and treatments.


2018 ◽  
Vol 35 (11) ◽  
pp. 1210-1228 ◽  
Author(s):  
Alistair S. Brown ◽  
Mark J. Calcott ◽  
Jeremy G. Owen ◽  
David F. Ackerley

Salutary lessons from recent progress in re-engineering non-ribosomal peptide synthetase assembly lines, emphasizing effective strategies and key protein–protein interactions.


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