THPdb: Database of FDA-approved peptide and protein therapeutics

Biomaterials Science

Recent advances in biomaterial delivery vehicles have increased the ability to tailor precise protein delivery to restore normal healing cascades and stimulate robust tissue repair.

2020

Increasing use of therapeutic peptides for treating cancer has received considerable attention of the scientific community in the recent years. The present study describes the in silico model developed for predicting and designing anticancer peptides (ACPs). ACPs residue composition analysis revealed the preference of A, F, K, L and W. Positional preference analysis revealed that residue A, F and K are preferred at N-terminus and residue L and K are preferred at C-terminus. Motif analysis revealed the presence of motifs like LAKLA, AKLAK, FAKL, LAKL in ACPs. Prediction models were developed using various input features and implementing different machine learning classifiers on two datasets main and alternate dataset. In the case of main dataset, ETree Classifier based model developed using dipeptide composition achieved maximum MCC of 0.51 and 0.83 AUROC on the training dataset. In the case of alternate dataset, ETree Classifier based model developed using amino acid composition performed best and achieved the highest MCC of 0.80 and AUROC of 0.97 on the training dataset. Models were trained and tested using five-fold cross validation technique and their performance was also evaluated on the validation dataset. Best models were implemented in the webserver AntiCP 2.0, freely available at https://webs.iiitd.edu.in/raghava/anticp2. The webserver is compatible with multiple screens such as iPhone, iPad, laptop, and android phones. The standalone version of the software is provided in the form of GitHub package as well as in docker technology.

Molecules

During recent decades, the market for peptide-based drugs, including antimicrobial peptides, has vastly extended and evolved. These drugs can be useful in treatment of various types of disorders, e.g., cancer, autoimmune diseases, infections, and non-healing wounds. Although peptides are less immunogenic than other biologic therapeutics, they can still induce immune responses and cause allergies. It is important to evaluate the immunogenic and allergic potential of peptides before they are forwarded to the expensive stages of clinical trials. The process of the evaluation of immunogenicity and cytotoxicity is complicated, as in vitro models and bioinformatics tools cannot fully simulate situations in the clinic. Nevertheless, several potentially promising tests for the preclinical evaluation of peptide drugs have been implemented (e.g., cytotoxicity assays, the basophil activation test, and lymphocyte activation assays). In this review, we focus on strategies for evaluation of the allergic potential of peptide-based therapeutics.

Molecules

Nowadays, cancer has become the second highest leading cause of death, and it is expected to continue to affect the population in forthcoming years. Additionally, treatment options will become less accessible to the public as cases continue to grow and disease mechanisms expand. Hence, specific candidates with confirmed anticancer effects are required to develop new drugs. Among the novel therapeutic options, proteins are considered a relevant source, given that they have bioactive peptides encrypted within their sequences. These bioactive peptides, which are molecules consisting of 2–50 amino acids, have specific activities when administered, producing anticancer effects. Current databases report the effects of peptides. However, uncertainty is found when their molecular mechanisms are investigated. Furthermore, analyses addressing their interaction networks or their directly implicated mechanisms are needed to elucidate their effects on cancer cells entirely. Therefore, relevant p...

PloS one, 2018

This paper describes a web server developed for designing therapeutic peptides with desired half-life in blood. In this study, we used 163 natural and 98 modified peptides whose half-life has been determined experimentally in mammalian blood, for developing in silico models. Firstly, models have been developed on 261 peptides containing natural and modified residues, using different chemical descriptors. The best model using 43 PaDEL descriptors got a maximum correlation of 0.692 between the predicted and the actual half-life peptides. Secondly, models were developed on 163 natural peptides using amino acid composition feature of peptides and achieved a maximum correlation of 0.643. Thirdly, models were developed on 163 natural peptides using chemical descriptors and attained a maximum correlation of 0.743 using 45 selected PaDEL descriptors. In order to assist researchers in the prediction and designing of half-life of peptides, the models developed have been integrated into PlifeP...

International Journal of Molecular Sciences

Antimicrobial peptides (AMPs) are distributed across all kingdoms of life and are an indispensable component of host defenses. They consist of predominantly short cationic peptides with a wide variety of structures and targets. Given the ever-emerging resistance of various pathogens to existing antimicrobial therapies, AMPs have recently attracted extensive interest as potential therapeutic agents. As the discovery of new AMPs has increased, many databases specializing in AMPs have been developed to collect both fundamental and pharmacological information. In this review, we summarize the sources, structures, modes of action, and classifications of AMPs. Additionally, we examine current AMP databases, compare valuable computational tools used to predict antimicrobial activity and mechanisms of action, and highlight new machine learning approaches that can be employed to improve AMP activity to combat global antimicrobial resistance.

International Journal of Molecular Sciences, 2021

Peptide-based drugs are an attractive class of therapeutic agents, recently recognized by the pharmaceutical industry. These molecules are currently being used in the development of innovative therapies for diverse health conditions, including tropical diseases such as leishmaniasis. Despite its socioeconomic influence on public health, leishmaniasis remains long-neglected and categorized as a poverty-related disease, with limited treatment options. Peptides with antileishmanial effects encountered to date are a structurally heterogeneous group, which can be found in different natural sources—amphibians, reptiles, insects, bacteria, marine organisms, mammals, plants, and others—or inspired by natural toxins or proteins. This review details the biochemical and structural characteristics of over one hundred peptides and their potential use as molecular frameworks for the design of antileishmanial drug leads. Additionally, we detail the main chemical modifications or substitutions of a...

Nano Research, 2022

Functional proteins are the most versatile macromolecules. They can be obtained by extraction from natural sources or by genetic engineering technologies. The outstanding selectivity, specificity, binding activity, and biocompatibility endow engineered proteins with outstanding performance for disease therapy. Nevertheless, their stability is dramatically impaired in blood circulation, hindering clinical translations. Thus, many strategies have been developed to improve the stability, efficacy, bioavailability, and productivity of therapeutic proteins for clinical applications. In this review, we summarize the recent progress in the fabrication and application of therapeutic proteins. We first introduce various strategies for improving therapeutic efficacy via bioengineering and nanoassembly. Furthermore, we highlight their diverse applications as growth factors, nanovaccines, antibody-based drugs, bioimaging molecules, and cytokine receptor antagonists. Finally, a summary and perspective for the future development of therapeutic proteins are presented.

Pharmaceutics, 2020

Proteins and peptides have emerged in recent years to treat a wide range of multifaceted diseases such as cancer, diabetes and inflammation. The emergence of polypeptides has yielded advancements in the fields of biopharmaceutical production and formulation. Polypeptides often display poor pharmacokinetics, limited permeability across biological barriers, suboptimal biodistribution, and some proclivity for immunogenicity. Frequent administration of polypeptides is generally required to maintain adequate therapeutic levels, which can limit efficacy and compliance while increasing adverse reactions. Many strategies to increase the duration of action of therapeutic polypeptides have been described with many clinical products having been developed. This review describes approaches to optimise polypeptide delivery organised by the commonly used routes of administration. Future innovations in formulation may hold the key to the continued successful development of proteins and peptides wit...

Computational and Structural Biotechnology Journal

Protein seldom performs biological activities in isolation. Understanding the protein-protein interactions' physical rewiring in response to pathological conditions or pathogen infection can help advance our comprehension of disease etiology, progression, and pathogenesis, which allow us to explore the alternate route to control the regulation of key target interactions, timely and effectively. Nonalcoholic steatohepatitis (NASH) is now a global public health problem exacerbated due to the lack of appropriate treatments. The most advanced anti-NASH lead compound (selonsertib) is withdrawn, though it is able to inhibit its target Apoptosis signal-regulating kinase 1 (ASK1) completely, indicating the necessity to explore alternate routes rather than complete inhibition. Understanding the interaction fingerprints of endogenous regulators at the molecular level that underpin disease formation and progression may spur the rationale of designing therapeutic strategies. Based on our analysis and thorough literature survey of the various key regulators and PTMs, the current review emphasizes PPI-based drug discovery's relevance for NASH conditions. The lack of structural detail (interface sites) of ASK1 and its regulators makes it challenging to characterize the PPI interfaces. This review summarizes key regulators interaction fingerprinting of ASK1, which can be explored further to restore the homeostasis from its hyperactive states for therapeutics intervention against NASH.

International Journal of Molecular Sciences, 2021

Topical and transdermal delivery systems are of undeniable significance and ubiquity in healthcare, to facilitate the delivery of active pharmaceutical ingredients, respectively, onto or across the skin to enter systemic circulation. From ancient ointments and potions to modern micro/nanotechnological devices, a variety of approaches has been explored over the ages to improve the skin permeation of diverse medicines and cosmetics. Amongst the latest investigational dermal permeation enhancers, ionic liquids have been gaining momentum, and recent years have been prolific in this regard. As such, this review offers an outline of current methods for enhancing percutaneous permeation, highlighting selected reports where ionic liquid-based approaches have been investigated for this purpose. Future perspectives on use of ionic liquids for topical delivery of bioactive peptides are also presented.

International Journal of Nanomedicine

To conjugate different degree of saturation of C18 fatty acids (stearic acid, oleic acid, and linoleic acid) with the hydroxyl groups of leuprolide acetate (LEU acetate) and to investigate the controlled release and enhanced permeability through self-assembled nanoparticles (L18FNs). Methods: Yamaguchi esterification with benzoyl chloride and DMAP (4-Dimethylaminopyridine) allowed the conjugation of the fatty acid to the hydroxyl group of LEU. The three conjugates were then designated as stearic acid-conjugated LEU, LSC, oleic acidconjugated LEU, LOC, and linoleic acid-conjugated LEU, LLC, respectively. The conjugates (L18FCs) were purified using preparative HPLC (Prep-HPLC) and identified through various instrumental analyses. Results: The zeta potential, particle size, and morphology of each L18FNs were evaluated. In the case of LSNs, the zeta potential value was relatively low and the particle size was larger than LONs and LLNs owing to the higher hydrophobicity of saturated fatty chain, while the LLNs showed a higher zeta potential and smaller particle size. In human plasma, LLC showed the fastest degradation rate with the highest accumulative drug release. The permeability of L18FNs was analyzed through the Franz diffusion cell experiment, confirming that the degree of saturation of fatty acids affects the permeability of LFNs. While the permeability of LSNs was not significantly enhanced due to higher particle size after nanonization, LONs and LLNs increased 1.56 and 1.85 times in permeation, respectively, compared to LEU. Conclusion: Utilization of different degree of saturation of fatty acids to conjugate a peptide drug could provide pharmaceutical versatility via self-assembly and modification of physicochemical properties.

2019

MotivationIn last three decades, a wide range of protein descriptors/features have been discovered to annotate a protein with high precision. A wide range of features have been integrated in numerous software packages (e.g., PROFEAT, PyBioMed, iFeature, protr, Rcpi, propy) to predict function of a protein. These features are not suitable to predict function of a protein at residue level such as prediction of ligand binding residues, DNA interacting residues, post translational modification etc.ResultsIn order to facilitate scientific community, we have developed a software package that computes more than 50,000 features, important for predicting function of a protein and its residues. It has five major modules for computing; composition-based features, binary profiles, evolutionary information, structure-based features and patterns. The composition-based module allows user to compute; i) simple compositions like amino acid, dipeptide, tripeptide; ii) Properties based compositions; i...

Journal of Nanotechnology, 2020

Treatment of brain diseases is always limited by the physiological nature of the highly selective blood-brain barrier (BBB) and the electrostatic charge of the nanoporous extracellular matrix. Nanomedical application provides a promising drug delivery revolution for the treatment of neurodegenerative diseases (NDDs). It depends on improving the pharmacokinetic distribution of drugs through the central nervous system. Nanotechnology offers various forms of nanoparticles, and these nanoparticles have brain-targeted and long-acting properties with minimal systemic adverse effects and motor complications. Gene delivery vehicles and nanocarriers including neurotrophic factors are promising therapeutics for many NDDs, and they can modulate neuronal survival and synaptic connectivity. Neurotrophic factors when integrated with the nanotechnological approaches can pass the BBB merely, representing a significant challenging track. Clinical trials proved that levodopa nanoparticles cause littl...

Frontiers in microbiology, 2018

This paper describesmodels developed using a wide range of peptide features for predicting antifungal peptides (AFPs). Our analyses indicate that certain types of residue (e.g., C, G, H, K, R, Y) are more abundant in AFPs. The positional residue preference analysis reveals the prominence of the particular type of residues (e.g., R, V, K) at N-terminus and a certain type of residues (e.g., C, H) at C-terminus. In this study, models have been developed for predicting AFPs using a wide range of peptide features (like residue composition, binary profile, terminal residues). The support vector machine based model developed using compositional features of peptides achieved maximum accuracy of 88.78% on the training dataset and 83.33% on independent or validation dataset. Our model developed using binary patterns of terminal residues of peptides achieved maximum accuracy of 84.88% on training and 84.64% on validation dataset. We benchmark models developed in this study and existing methods...

Frontiers in Pharmacology, 2018

Tuberculosis is one of the leading cause of death worldwide, particularly due to evolution of drug resistant strains. Antitubercular peptides may provide an alternate approach to combat antibiotic tolerance. Sequence analysis reveals that certain residues (e.g., Lysine, Arginine, Leucine, Tryptophan) are more prevalent in antitubercular peptides. This study describes the models developed for predicting antitubercular peptides by using sequence features of the peptides. We have developed support vector machine based models using different sequence features like amino acid composition, binary profile of terminus residues, dipeptide composition. Our ensemble classifiers that combines models based on amino acid composition and N5C5 binary pattern, achieves highest Acc of 73.20% with 0.80 AUROC on our main dataset. Similarly, the ensemble classifier achieved maximum Acc 75.62% with 0.83 AUROC on secondary dataset. Beside this, hybrid model achieves Acc of 75.87 and 78.54% with 0.83 and 0.86 AUROC on main and secondary dataset, respectively. In order to facilitate scientific community in designing of antitubercular peptides, we implement above models in a user friendly webserver (http:// webs.iiitd.edu.in/raghava/antitbpred/).

Pharmaceuticals

The therapeutic potential of venom-derived peptides, such as bioactive peptides (BAPs), is determined by specificity, stability, and pharmacokinetics properties. BAPs, including anti-infective or antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs), share several physicochemical characteristics and are potential alternatives to antibiotic-based therapies and drug delivery systems, respectively. This study used in silico methods to predict AMPs and CPPs derived from natterins from the venomous fish Thalassophryne nattereri. Fifty-seven BAPs (19 AMPs, 8 CPPs, and 30 AMPs/CPPs) were identified using the web servers CAMP, AMPA, AmpGram, C2Pred, and CellPPD. The physicochemical properties were analyzed using ProtParam, PepCalc, and DispHred tools. The membrane-binding potential and cellular location of each peptide were analyzed using the Boman index by APD3, and TMHMM web servers. All CPPs and two AMPs showed high membrane-binding potential. Fifty-four peptides were locate...

International Journal of Peptide Research and Therapeutics, 2018

Biologically active peptides and proteins have wide applications as therapeutic agents as well as diagnostics. Parathyroid hormone (PTH), a polypeptide secreted by the parathyroid chief cells has been found to be an effective therapeutic protein for the treatment of osteoporosis. PTH as an anabolic agent and a potent regulator of ionized calcium and phosphate plays a pivotal role in maintaining active vitamin D metabolite levels in the circulating blood. Though licensed PTH is available in two forms as teriparatide having 1-34 amino acids and intact hormone having 1-84 aminoacids, due to short plasma half-life and low activity, their therapeutic purpose has been limited. Protein engineering approaches like PEGylation, conjugation with antibody complexes, and fusion proteins as well as amino terminal modification of intact or truncated PTH has helped to develop PTH and its modified analogs with improved therapeutic value and multitude functions in various fields of medicine. This review covers the significant role of PTH in osteoblast signaling mechanism, regulation of PTH secretion and its transcription, modifications in PTH along with its functional efficacy in different medical areas.

Frontiers in Pharmacology, 2020

Tardigrades are microscopic animals well-known for their stress tolerance, including the ability to survive desiccation. This survival requires cytosolic abundant heat soluble (CAHS) proteins. CAHS D protects enzymes from desiccation-and lyophilization-induced inactivation in vitro and has the potential to stabilize protein-based therapeutics, including vaccines. Here, we investigate whether purified recombinant CAHS D causes hemolysis or a toxic or immunogenic response following intraperitoneal injection in mice. CAHS D did not cause hemolysis, and all mice survived the 28-day monitoring period. The mice gained weight normally and developed anti-CAHS D antibodies but did not show upregulation of the inflammatory cytokines interleukin-6 and tumor necrosis factor alpha. In summary, CAHS D is not toxic and does not promote an inflammatory immune response in mice under the conditions used here, suggesting the reasonability of further study for use as stabilizers of protein-based therapeutics.

International Journal of Molecular Sciences

Poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) enhance the delivery of therapeutic enzymes for replacement therapy of lysosomal storage disorders. Previous studies examined NPs encapsulating or coated with enzymes, but these formulations have never been compared. We examined this using hyaluronidase (HAse), deficient in mucopolysaccharidosis IX, and acid sphingomyelinase (ASM), deficient in types A–B Niemann–Pick disease. Initial screening of size, PDI, ζ potential, and loading resulted in the selection of the Lactel II co-polymer vs. Lactel I or Resomer, and Pluronic F68 surfactant vs. PVA or DMAB. Enzyme input and addition of carrier protein were evaluated, rendering NPs having, e.g., 181 nm diameter, 0.15 PDI, −36 mV ζ potential, and 538 HAse molecules encapsulated per NP. Similar NPs were coated with enzyme, which reduced loading (e.g., 292 HAse molecules/NP). NPs were coated with targeting antibodies (> 122 molecules/NP), lyophilized for storage without alterations, a...

Angewandte Chemie International Edition, 2020

Proteolytic stability assessment is increasingly viewed as a fundamental component of peptide characterization, arguably of comparable importance as efficacy and toxicity data. A literature survey over the last decade reveals steady growth in the stability information available. However, it also uncovers two significant problems that hinder proper data comparison: 1) the use of different stability assays, and 2) the differences in how stability information is reported. In this Viewpoint, we present results from a database metaanalysis as well as concerns about the stability assessments published so far. We also suggest guidelines for a proper discussion between experts in the field on how to improve data readability so that peptide stability, an often-missing parameter in older literature, is adequately reported to take maximum advantage of it.

Pharmaceutics, 2021

Enzyme nanoencapsulation holds an enormous potential to develop new therapeutic approaches to a large set of human pathologies including cancer, infectious diseases and inherited metabolic disorders. However, enzyme formulation has been limited by the need to maintain the catalytic function, which is governed by protein conformation. Herein we report the rational design of a delivery system based on chitosan for effective encapsulation of a functionally and structurally complex human metabolic enzyme through ionic gelation with tripolyphosphate. The rationale was to use a mild methodology to entrap the multimeric multidomain 200 kDa human phenylalanine hydroxylase (hPAH) in a polyol-like matrix that would allow an efficient maintenance of protein structure and function, avoiding formulation stress conditions. Through an in silico and in vitro based development, the particulate system was optimized with modulation of nanomaterials protonation status, polymer, counterion and protein r...

Frontiers in Molecular Biosciences, 2022

Amidst rising cases of antimicrobial resistance, antimicrobial peptides (AMPs) are regarded as a promising alternative to traditional antibiotics. Even so, poor pharmacokinetic profiles of certain AMPs impede their utility necessitating, a careful assessment of potential AMPs' absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties during novel lead exploration. Accordingly, the present study utilized ADMET scores to profile seven previously isolated African catfish antimicrobial peptides (ACAPs). After profiling, the peptides were docked against approved bacterial protein targets to gain insight into their possible mode of action. Promising ACAPs were then chemically synthesized, and their antibacterial activity was validated in vitro utilizing the broth dilution method. All seven examined antimicrobial peptides passed the ADMET screening, with two (ACAP-IV and ACAP-V) exhibiting the best ADMET profile scores. The ACAP-V had a higher average binding energy (−8.47 kcal/mol) and average global energy (−70.78 kcal/mol) compared to ACAP-IV (−7.60 kcal/mol and −57.53 kcal/mol), with the potential to penetrate and disrupt bacterial cell membrane (PDB Id: 2w6d). Conversely, ACAP-IV peptide had higher antibacterial activity against E. coli and S. aureus

International Journal of Molecular Sciences

The emergence and growth of bacterial resistance to antibiotics poses an enormous threat to humanity in the future. In this regard, the discovery of new antibiotics and the improvement of existing ones is a priority task. In this study, we proposed the synthesis of new polymeric conjugates of polymyxin B, which is a clinically approved but limited-use peptide antibiotic. In particular, three carboxylate-bearing polymers and one synthetic glycopolymer were selected for conjugation with polymyxin B (PMX B), namely, poly(α,L-glutamic acid) (PGlu), copolymer of L-glutamic acid and L-phenylalanine (P(Glu-co-Phe)), copolymer of N-vinyl succinamic acid and N-vinylsuccinimide (P(VSAA-co-VSI)), and poly(2-deoxy-2-methacrylamido-D-glucose) (PMAG). Unlike PGlu and PMAG, P(Glu-co-Phe) and P(VSAA-co-VSI) are amphiphilic and form nanoparticles in aqueous media. A number of conjugates with different polymyxin B loading were synthesized and characterized. In addition, the complex conjugates of PGLu...

Pharmaceuticals

The entry of proteins through the cell membrane is challenging, thus limiting their use as potential therapeutics. Seven cell-penetrating peptides, designed in our laboratory, were evaluated for the delivery of proteins. Fmoc solid-phase peptide synthesis was utilized for the synthesis of seven cyclic or hybrid cyclic–linear amphiphilic peptides composed of hydrophobic (tryptophan (W) or 3,3-diphenylalanine (Dip) and positively-charged arginine (R) residues, such as [WR]4, [WR]9, [WWRR]4, [WWRR]5, [(RW)5K](RW)5, [R5K]W7, and [DipR]5. Confocal microscopy was used to screen the peptides as a protein delivery system of model cargo proteins, green and red fluorescein proteins (GFP and RFP). Based on the confocal microscopy results, [WR]9 and [DipR]5 were found to be more efficient among all the peptides and were selected for further studies. [WR]9 (1–10 µM) + protein (GFP and RFP) physical mixture did not show high cytotoxicity (>90% viability) in triple-negative breast cancer cells ...

International Journal of Molecular Sciences, 2022

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

International Journal of Molecular Sciences

Protein–protein interfaces play fundamental roles in the molecular mechanisms underlying pathophysiological pathways and are important targets for the design of compounds of therapeutic interest. However, the identification of binding sites on protein surfaces and the development of modulators of protein–protein interactions still represent a major challenge due to their highly dynamic and extensive interfacial areas. Over the years, multiple strategies including structural, computational, and combinatorial approaches have been developed to characterize PPI and to date, several successful examples of small molecules, antibodies, peptides, and aptamers able to modulate these interfaces have been determined. Notably, peptides are a particularly useful tool for inhibiting PPIs due to their exquisite potency, specificity, and selectivity. Here, after an overview of PPIs and of the commonly used approaches to identify and characterize them, we describe and evaluate the impact of chemical...

International Journal of Peptide Research and Therapeutics

In recent years, the occurrence of a wide variety of drug-resistant diseases has led to an increase in interest in alternate therapies. Peptide-based drugs as an alternate therapy hold researchers' attention in various therapeutic fields such as neurology, dermatology, oncology, metabolic diseases, etc. Previously, they had been overlooked by pharmaceutical companies due to certain limitations such as proteolytic degradation, poor membrane permeability, low oral bioavailability, shorter half-life, and poor target specificity. Over the last two decades, these limitations have been countered by introducing various modification strategies such as backbone and side-chain modifications, amino acid substitution, etc. which improve their functionality. This has led to a substantial interest of researchers and pharmaceutical companies, moving the next generation of these therapeutics from fundamental research to the market. Various chemical and computational approaches are aiding the production of more stable and long-lasting peptides guiding the formulation of novel and advanced therapeutic agents. However, there is not a single article that talks about various peptide design approaches i.e., in-silico and in-vitro along with their applications and strategies to improve their efficacy. In this review, we try to bring different aspects of peptide-based therapeutics under one article with a clear focus to cover the missing links in the literature. This review draws emphasis on various in-silico approaches and modification-based peptide design strategies. It also highlights the recent progress made in peptide delivery methods important for their enhanced clinical efficacy. The article would provide a bird's-eye view to researchers aiming to develop peptides with therapeutic applications.

Frontiers in Molecular Biosciences, 2021

Large contact surfaces of protein–protein interactions (PPIs) remain to be an ongoing issue in the discovery and design of small molecule modulators. Peptides are intrinsically capable of exploring larger surfaces, stable, and bioavailable, and therefore bear a high therapeutic value in the treatment of various diseases, including cancer, infectious diseases, and neurodegenerative diseases. Given these promising properties, a long way has been covered in the field of targeting PPIsviapeptide design strategies.In silicotools have recently become an inevitable approach for the design and optimization of these interfering peptides. Various algorithms have been developed to scrutinize the PPI interfaces. Moreover, different databases and software tools have been created to predict the peptide structures and their interactions with target protein complexes. High-throughput screening of large peptide libraries against PPIs; “hotspot” identification; structure-based and off-structure appro...

Pharmaceutics

Peptides can act as targeting molecules, analogously to oligonucleotide aptamers and antibodies. They are particularly efficient in terms of production and stability in physiological environments; in recent years, they have been increasingly studied as targeting agents for several diseases, from tumors to central nervous system disorders, also thanks to the ability of some of them to cross the blood–brain barrier. In this review, we will describe the techniques employed for their experimental and in silico design, as well as their possible applications. We will also discuss advancements in their formulation and chemical modifications that make them even more stable and effective. Finally, we will discuss how their use could effectively help to overcome various physiological problems and improve existing treatments.

Journal of the American Chemical Society, 2022

Native ion mobility mass spectrometry is potentially useful for the biophysical characterization of proteins, as the electrospray charge state distribution and the collision cross section distribution depend on their solution conformation. We examine here the charging and gas-phase conformation of multi-subunit therapeutic proteins comprising globular subunits tethered by disordered linkers. The charge and collision cross section distributions are multimodal, suggesting several conformations in solution, as confirmed by solution hydrogen/deuterium exchange. The most intriguing question is the ionization mechanism of these structures: a fraction of the population does not follow the charged residue mechanism, but cannot ionize by pure chain ejection either. We deduce that a hybrid mechanism is possible, wherein globular subunits are ejected one at the time from a parent droplet. The charge vs. solvent accessible surface area correlations of denatured and intrinsically disordered proteins are also compatible with this "bead ejection mechanism", which we propose as a general tenet of biomolecule electrospray.

Acta Biomaterialia, 2021

The possibility to conjugate tumor-targeted cytotoxic nanoparticles and conventional antitumoral drugs in single pharmacological entities would open a wide spectrum of opportunities in nanomedical oncology. This principle has been explored here by using CXCR4-targeted self-assembling protein nanoparticles based on two potent microbial toxins, the exotoxin A from Pseudomonas aeruginosa and the diphtheria toxin from Corynebacterium diphtheriae, to which oligo-floxuridine and monomethyl auristatin E respectively have been chemically coupled. The resulting multifunctional hybrid nanoconjugates, with a hydrodynamic size of around 50 nm, are stable and internalize target cells with a biological impact. Although the chemical conjugation minimizes the cytotoxic activity of the protein partner in the complexes, the concept of drug combination proposed here is fully feasible and highly promising when considering multiple drug treatments aimed to higher effectiveness or when facing the therapy of cancers with acquired resistance to classical drugs. Statement of significance Tumor-targeted cytotoxic nanoparticles formed by self-assembling toxins have been chemically conjugated with conventional antitumoral drugs, resulting in CXCR4-targeted, stable pharmacological entities at the nanoscale. Under this premise, the exotoxin A from Pseudomonas aeruginosa and the diphtheria toxin from Corynebacterium diphtheria have been combined with oligo-floxuridine and monomethyl auristatin E respectively, to be tested in cell culture models of CXCR4 + human cancers. The resulting data demonstrate that the proposed engineering principle is fully feasible but that the chemical conjugation based on lysine residues might minimize protein performance if the coupling residues are located in critical domains of the partner protein.

Advanced Therapeutics, 2021

From recombinant insulin to monoclonal antibodies, proteins have become essential drugs in the therapeutic arsenal and respond to a broad spectrum of diseases. While commercially available proteins have an extracellular activity, intracellular targets can be a powerful alternative to treat many pathologies such as cancers and immune disorders, but also infectious diseases. Nevertheless, to enter the cell and reach the target organelle or molecule, therapeutic proteins have to face numerous barriers (internalization, endosomal escape, and cytoplasm trafficking). In view of the fragile nature and high heterogeneity of proteins in terms of size, charge, and hydrophilic/lipophilic profile, the development of an efficient cytoplasm delivery system remains a long‐standing challenge. The discovery of several gene editing tools (Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR), involving caspase 9 (Cas9) protein (CRISPRCas9), transcription activator‐like effectors (TALEs) o...

INDIAN DRUGS, 2021

The significant scientific work on the development of bio-active compound databases, computational technologies, and the integration of Information Technology with Biotechnology has brought a revolution in the domain of drug discovery. These tools facilitate the medicinal plant-based in silico drug discovery, which has become the frontier of pharmacological science. In this review article, we elucidate the methodology of in silico drug discovery for the medicinal plants and present an outlook on recent tools and technologies. Further, we explore the multi-component, multi-target, and multi-pathway mechanism of the bio-active compounds with the help of Network Pharmacology, which enables us to create a topological network between drug, target, gene, pathway, and disease.

Therapeutic Delivery, 2020

The advancement of the oral route for macromolecules has gained a lot of attention due to its noninvasive nature, safe and challenging in active research but with limited success. Oral administration poses challenges due to poor solubility, short half-life, quick elimination and the physical, chemical and biological barriers of the gastrointestinal tract. Approaches of past for improving oral absorption, such as enhancers, mucoadhesive delivery and enzyme inhibitors have been taken over by novel approaches like advanced liposomes, self-nanoemulsifying drug delivery system, nanoparticles and targeted delivery. Eudratech™ Pep, Peptelligence, Rani Pill and Pharm Film are the emerging technologies for delivering oral proteins and peptide. Calcitonin, semaglutide and octreotide are the peptides available in the market for oral delivery as outcomes of these technologies.

Cancer Research, 2022

We developed a new systemic approach that will improve the treatment outcomes of bladder cancer by covering the entire urinary system and prolonging tumor-drug exposure. Intravenous administration of drug-Bdd conjugates