scholarly journals A Comprehensive Review on Current Advances in Peptide Drug Development and Design

2019 ◽  
Vol 20 (10) ◽  
pp. 2383 ◽  
Author(s):  
Andy Chi-Lung Lee ◽  
Janelle Louise Harris ◽  
Kum Kum Khanna ◽  
Ji-Hong Hong
Keyword(s):  
Drug Development ◽  
Binding Affinity ◽  
Protein Interactions ◽  
Binding Sites ◽  
Drug Targets ◽  
Peptide Drug ◽  
Protein Protein Interactions ◽  
Cellular Functions ◽  
Endogenous Protein ◽  
Binding Interfaces

Protein–protein interactions (PPIs) execute many fundamental cellular functions and have served as prime drug targets over the last two decades. Interfering intracellular PPIs with small molecules has been extremely difficult for larger or flat binding sites, as antibodies cannot cross the cell membrane to reach such target sites. In recent years, peptides smaller size and balance of conformational rigidity and flexibility have made them promising candidates for targeting challenging binding interfaces with satisfactory binding affinity and specificity. Deciphering and characterizing peptide–protein recognition mechanisms is thus central for the invention of peptide-based strategies to interfere with endogenous protein interactions, or improvement of the binding affinity and specificity of existing approaches. Importantly, a variety of computation-aided rational designs for peptide therapeutics have been developed, which aim to deliver comprehensive docking for peptide–protein interaction interfaces. Over 60 peptides have been approved and administrated globally in clinics. Despite this, advances in various docking models are only on the merge of making their contribution to peptide drug development. In this review, we provide (i) a holistic overview of peptide drug development and the fundamental technologies utilized to date, and (ii) an updated review on key developments of computational modeling of peptide–protein interactions (PepPIs) with an aim to assist experimental biologists exploit suitable docking methods to advance peptide interfering strategies against PPIs.

scholarly journals Unbiased Identification of Extracellular Protein–Protein Interactions for Drug Target and Biologic Drug Discovery

2021 ◽  
Author(s):  
Shengya Cao ◽  
Nadia Martinez-Martin
Keyword(s):  
Drug Discovery ◽  
Protein Interactions ◽  
Drug Target ◽  
Drug Targets ◽  
Extracellular Protein ◽  
Protein Protein Interactions ◽  
Cellular Functions ◽  
Drug Target Discovery ◽  
Technological Improvements ◽  
Targeted Drug Discovery

Technological improvements in unbiased screening have accelerated drug target discovery. In particular, membrane-embedded and secreted proteins have gained attention because of their ability to orchestrate intercellular communication. Dysregulation of their extracellular protein–protein interactions (ePPIs) underlies the initiation and progression of many human diseases. Practically, ePPIs are also accessible for modulation by therapeutics since they operate outside of the plasma membrane. Therefore, it is unsurprising that while these proteins make up about 30% of human genes, they encompass the majority of drug targets approved by the FDA. Even so, most secreted and membrane proteins remain uncharacterized in terms of binding partners and cellular functions. To address this, a number of approaches have been developed to overcome challenges associated with membrane protein biology and ePPI discovery. This chapter will cover recent advances that use high-throughput methods to move towards the generation of a comprehensive network of ePPIs in humans for future targeted drug discovery.

scholarly journals Avidity observed between a bivalent inhibitor and an enzyme monomer with a single active site

2021 ◽  
Author(s):  
Shiran Lacham-Hartman ◽  
Yulia Shmidov ◽  
Evette S. Radisky ◽  
Ronit Bitton ◽  
David B. Lukatsky ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Affinity ◽  
Protein Interactions ◽  
Protein Complex ◽  
Binding Sites ◽  
Biological Interactions ◽  
Protein Protein Interactions ◽  
Regulatory Pathways ◽  
Multiple Binding Sites ◽  
Ligand Binding Sites

AbstractAlthough myriad protein–protein interactions in nature use polyvalent binding, in which multiple ligands on one entity bind to multiple receptors on another, to date an affinity advantage of polyvalent binding has been demonstrated experimentally only in cases where the target receptor molecules are clustered prior to complex formation. Here, we demonstrate cooperativity in binding affinity (i.e., avidity) for a protein complex in which an engineered dimer of the amyloid precursor protein inhibitor (APPI), possessing two fully functional inhibitory loops, interacts with mesotrypsin, a soluble monomeric protein that does not self-associate or cluster spontaneously. We found that each inhibitory loop of the purified APPI homodimer was over three-fold more potent than the corresponding loop in the monovalent APPI inhibitor. This observation is consistent with a suggested mechanism whereby the two APPI loops in the homodimer simultaneously and reversibly bind two corresponding mesotrypsin monomers to mediate mesotrypsin dimerization. We propose a simple model for such dimerization that quantitatively explains the observed cooperativity in binding affinity. Binding cooperativity in this system reveals that the valency of ligands may affect avidity in protein–protein interactions including those of targets that are not surface-anchored and do not self-associate spontaneously. In this scenario, avidity may be explained by the enhanced concentration of ligand binding sites in proximity to the monomeric target, which may favor rebinding of the multiple ligand binding sites with the receptor molecules upon dissociation of the protein complex.Impact statementLacham-Hartman et al. demonstrate enhancement of binding affinity through avidity in a complex between a bivalent ligand and a soluble monomeric target with a single binding site. Avidity effects have previously been demonstrated only for clustered receptor molecules presenting multiple binding sites. Our model may explain how polyvalent ligands can agonize or antagonize biological interactions involving nonclustered target molecules that are crucial for intra- and extracellular structural, metabolic, signaling, and regulatory pathways.

scholarly journals Targeting the cryptic sites: NMR-based strategy to improve protein druggability by controlling the conformational equilibrium

2020 ◽  
Vol 6 (40) ◽  
pp. eabd0480
Author(s):  
Yumiko Mizukoshi ◽  
Koh Takeuchi ◽  
Yuji Tokunaga ◽  
Hitomi Matsuo ◽  
Misaki Imai ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Protein Interactions ◽  
Binding Sites ◽  
Drug Targets ◽  
Conformational Equilibrium ◽  
Wild Type ◽  
Protein Protein Interactions ◽  
Hit Rate ◽  
Open Conformation ◽  
Ligand Binding Sites

Cryptic ligand binding sites, which are not evident in the unligated structures, are beneficial in tackling with difficult but attractive drug targets, such as protein-protein interactions (PPIs). However, cryptic sites have thus far not been rationally pursued in the early stages of drug development. Here, we demonstrated by nuclear magnetic resonance that the cryptic site in Bcl-xL exists in a conformational equilibrium between the open and closed conformations under the unligated condition. While the fraction of the open conformation in the unligated wild-type Bcl-xL is estimated to be low, F143W mutation that is distal from the ligand binding site can substantially elevate the population. The F143W mutant showed a higher hit rate in a phage-display peptide screening, and the hit peptide bound to the cryptic site of the wild-type Bcl-xL. Therefore, by controlling the conformational equilibrium in the cryptic site, the opportunity to identify a PPI inhibitor could be improved.

scholarly journals In Silico Identification of Potential Druggable Binding Sites on CIN85 SH3 Domain

2021 ◽  
Vol 22 (2) ◽  
pp. 534
Author(s):  
Serena Vittorio ◽  
Thomas Seidel ◽  
Arthur Garon ◽  
Rosaria Gitto ◽  
Thierry Langer ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Binding Sites ◽  
Drug Targets ◽  
Migration And Invasion ◽  
Protein Protein Interactions ◽  
Physiological Processes ◽  
Binding Surface ◽  
Traditional Drug ◽  
Substantial Progress ◽  
Binding Pockets

Protein-protein interactions (PPIs) play a pivotal role in the regulation of many physiological processes. The dysfunction of some PPIs interactions led to the alteration of different biological pathways causing various diseases including cancer. In this context, the inhibition of PPIs represents an attractive strategy for the design of new antitumoral agents. In recent years, computational approaches were successfully used to study the interactions between proteins, providing useful hints for the design of small molecules able to modulate PPIs. Targeting PPIs presents several challenges mainly due to the large and flat binding surface that lack the typical binding pockets of traditional drug targets. Despite these hurdles, substantial progress has been made in the last decade resulting in the identification of PPI modulators where some of them even found clinical use. This study focuses on MUC1-CIN85 PPI which is involved in the migration and invasion of cancer cells. Particularly, we investigated the presence of druggable binding sites on the CIN85 surface which provided new insights for the structure-based design of novel MUC1-CIN85 PPI inhibitors as anti-metastatic agents.

scholarly journals Avidity observed between a bivalent inhibitor and an enzyme monomer with a single active site

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0249616
Author(s):  
Shiran Lacham-Hartman ◽  
Yulia Shmidov ◽  
Evette S. Radisky ◽  
Ronit Bitton ◽  
David B. Lukatsky ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Affinity ◽  
Protein Interactions ◽  
Protein Complex ◽  
Binding Sites ◽  
Protein Protein Interactions ◽  
Multiple Receptors ◽  
Ligand Binding Sites ◽  
Multiple Ligands ◽  
Multiple Ligand

Although myriad protein–protein interactions in nature use polyvalent binding, in which multiple ligands on one entity bind to multiple receptors on another, to date an affinity advantage of polyvalent binding has been demonstrated experimentally only in cases where the target receptor molecules are clustered prior to complex formation. Here, we demonstrate cooperativity in binding affinity (i.e., avidity) for a protein complex in which an engineered dimer of the amyloid precursor protein inhibitor (APPI), possessing two fully functional inhibitory loops, interacts with mesotrypsin, a soluble monomeric protein that does not self-associate or cluster spontaneously. We found that each inhibitory loop of the purified APPI homodimer was over three-fold more potent than the corresponding loop in the monovalent APPI inhibitor. This observation is consistent with a suggested mechanism whereby the two APPI loops in the homodimer simultaneously and reversibly bind two corresponding mesotrypsin monomers to mediate mesotrypsin dimerization. We propose a simple model for such dimerization that quantitatively explains the observed cooperativity in binding affinity. Binding cooperativity in this system reveals that the valency of ligands may affect avidity in protein–protein interactions including those of targets that are not surface-anchored and do not self-associate spontaneously. In this scenario, avidity may be explained by the enhanced concentration of ligand binding sites in proximity to the monomeric target, which may favor rebinding of the multiple ligand binding sites with the receptor molecules upon dissociation of the protein complex.

scholarly journals Allosteric Modulator Leads Hiding in Plain Site: Developing Peptide and Peptidomimetics as GPCR Allosteric Modulators

2021 ◽  
Vol 9 ◽  
Author(s):  
Keith M. Olson ◽  
John R. Traynor ◽  
Andrew Alt
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Drug Targets ◽  
Vital Role ◽  
Allosteric Modulators ◽  
Protein Protein Interactions ◽  
Good Tolerability ◽  
Endogenous Protein ◽  
Biased Signaling ◽  
G Protein Coupled

Allosteric modulators (AMs) of G-protein coupled receptors (GPCRs) are desirable drug targets because they can produce fewer on-target side effects, improved selectivity, and better biological specificity (e.g., biased signaling or probe dependence) than orthosteric drugs. An underappreciated source for identifying AM leads are peptides and proteins—many of which were evolutionarily selected as AMs—derived from endogenous protein-protein interactions (e.g., transducer/accessory proteins), intramolecular receptor contacts (e.g., pepducins or extracellular domains), endogenous peptides, and exogenous libraries (e.g., nanobodies or conotoxins). Peptides offer distinct advantages over small molecules, including high affinity, good tolerability, and good bioactivity, and specific disadvantages, including relatively poor metabolic stability and bioavailability. Peptidomimetics are molecules that combine the advantages of both peptides and small molecules by mimicking the peptide’s chemical features responsible for bioactivity while improving its druggability. This review 1) discusses sources and strategies to identify peptide/peptidomimetic AMs, 2) overviews strategies to convert a peptide lead into more drug-like “peptidomimetic,” and 3) critically analyzes the advantages, disadvantages, and future directions of peptidomimetic AMs. While small molecules will and should play a vital role in AM drug discovery, peptidomimetics can complement and even exceed the advantages of small molecules, depending on the target, site, lead, and associated factors.

scholarly journals Exploring Protein-Protein Interactions as Drug Targets for Anti-cancer Therapy with In Silico Workflows

2017 ◽  
pp. 221-236 ◽  
Author(s):  
Alexander Goncearenco ◽  
Minghui Li ◽  
Franco L. Simonetti ◽  
Benjamin A. Shoemaker ◽  
Anna R. Panchenko
Keyword(s):  
Cancer Therapy ◽  
Protein Interactions ◽  
In Silico ◽  
Drug Targets ◽  
Protein Protein Interactions ◽  
Anti Cancer

scholarly journals Theoretical models of inhibitory activity for inhibitors of protein–protein interactions: targeting menin–mixed lineage leukemia with small molecules

MedChemComm ◽  
2017 ◽  
Vol 8 (12) ◽  
pp. 2216-2227 ◽  
Author(s):  
Wiktoria Jedwabny ◽  
Szymon Kłossowski ◽  
Trupta Purohit ◽  
Tomasz Cierpicki ◽  
Jolanta Grembecka ◽  
...  
Keyword(s):  
Small Molecules ◽  
Binding Affinity ◽  
Protein Interactions ◽  
Empirical Model ◽  
Inhibitory Activity ◽  
Theoretical Models ◽  
Mixed Lineage Leukemia ◽  
Protein Protein Interactions ◽  
Model Based ◽  
Dispersion Terms

A computationally affordable, non-empirical model based on electrostatic multipole and dispersion terms successfully predicts the binding affinity of inhibitors of menin–MLL protein–protein interactions.

scholarly journals PF16 encodes a protein with armadillo repeats and localizes to a single microtubule of the central apparatus in Chlamydomonas flagella.

1996 ◽  
Vol 132 (3) ◽  
pp. 359-370 ◽  
Author(s):  
E F Smith ◽  
P A Lefebvre
Keyword(s):  
Protein Interactions ◽  
Insertional Mutagenesis ◽  
Flagellar Motility ◽  
Wild Type ◽  
Protein Protein Interactions ◽  
Cellular Functions ◽  
Central Pair ◽  
Central Apparatus ◽  
Immunofluorescence Labeling ◽  
Armadillo Repeats

Several studies have indicated that the central pair of microtubules and their associated structures play a significant role in regulating flagellar motility. To begin a molecular analysis of these components we have generated central apparatus-defective mutants in Chlamydomonas reinhardtii using insertional mutagenesis. One paralyzed mutant recovered in our screen, D2, is an allele of a previously identified mutant, pf16. Mutant cells have paralyzed flagella, and the C1 microtubule of the central apparatus is missing in isolated axonemes. We have cloned the wild-type PF16 gene and confirmed its identity by rescuing pf16 mutants upon transformation. The rescued pf16 cells were wild-type in motility and in axonemal ultrastructure. A full-length cDNA clone for PF16 was obtained and sequenced. Database searches using the predicted 566 amino acid sequence of PF16 indicate that the protein contains eight contiguous armadillo repeats. A number of proteins with diverse cellular functions also contain armadillo repeats including pendulin, Rch1, importin, SRP-1, and armadillo. An antibody was raised against a fusion protein expressed from the cloned cDNA. Immunofluorescence labeling of wild-type flagella indicates that the PF16 protein is localized along the length of the flagella while immunogold labeling further localizes the PF16 protein to a single microtubule of the central pair. Based on the localization results and the presence of the armadillo repeats in this protein, we suggest that the PF16 gene product is involved in protein-protein interactions important for C1 central microtubule stability and flagellar motility.

scholarly journals Engineered pH-Sensitive Protein G / IgG Interaction

2020 ◽  
Author(s):  
Ramesh K. Jha ◽  
Allison Yankey ◽  
Kalifa Shabazz ◽  
Leslie Naranjo ◽  
Nileena Velappan ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Protein Design ◽  
Protein Interactions ◽  
Rational Design ◽  
Protein G ◽  
Acidic Ph ◽  
Protein Protein Interactions ◽  
Natural Interface ◽  
Complex Stimuli ◽  
Igg Purification

ABSTRACTWhile natural protein-protein interactions have evolved to be induced by complex stimuli, rational design of interactions that can be switched-on-demand still remain challenging in the protein design world. Here, we demonstrate a computationally redesigned natural interface for improved binding affinity could further be mutated to adopt a pH switchable interaction. The redesigned interface of Protein G-IgG Fc domain, when incorporated with histidine and glutamic acid on Protein G (PrG-EHHE), showed a switch in binding affinity by 50-fold when pH was altered from mild acidic to mild basic. The wild type (WT) interface only showed negligible switch. The overall binding affinity at mild acidic pH for PrG-EHHE outperformed the WT PrG interaction. The new reagent PrG-EHHE will be revolutionary in IgG purification since the traditional method of using an extreme acidic pH for elution can be circumvented.Abstract Figure

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