Peptide Moiety Research Articles

Smart Accumulating Dual-Targeting Lipid Envelopes Equipping Oncolytic Adenovirus for Enhancing Cancer Gene Therapeutic Efficacy.

Systemic delivery of oncolytic adenovirus (oAd) for cancer gene therapy must overcome several limitations such as rapid clearance from the blood, nonspecific accumulation in the liver, and insufficient delivery to the tumor tissues. In the present report, a tumor microenvironment-triggered artificial lipid envelope composed of a pH-responsive sulfamethazine-based polymer (PUSSM)-conjugated phospholipid (DOPE-HZ-PUSSM) and another lipid decorated with epidermal growth factor receptor (EGFR) targeting peptide (GE11) (GE11-DOPE) was utilized to encapsulate replication-incompetent Ad (dAd) or oAd coexpressing short-hairpin RNA (shRNA) against Wnt5 (shWnt5) and decorin (dAd/LP-GE-PS or oAd/LP-GE-PS, respectively). In vitro studies demonstrated that dAd/LP-GE-PS transduced breast cancer cells in a pH-responsive and EGFR-specific manner, showing a higher level of transduction than naked Ad under a mildly acidic pH of 6.0 in EGFR-positive cell lines. In vivo biodistribution analyses revealed that systemic administration of oAd/LP-GE-PS leads to a significantly higher level of intratumoral virion accumulation compared to naked oAd, oAd encapsulated in a liposome without PUSSM or EGFR targeting peptide moiety (oAd/LP), or oAd encapsulated in a liposome with EGFR targeting peptide alone (oAd/LP-GE) in an EGFR overexpressing MDA-MB-468 breast tumor xenograft model, showing that both pH sensitivity and EGFR targeting ability were integral to effective systemic delivery of oAd. Further, systemic administration of all liposomal oAd formulations (oAd/LP, oAd/LP-GE, and oAd/LP-GE-PS) showed significantly attenuated hepatic accumulation of the virus compared to naked oAd. Collectively, our findings demonstrated that pH-sensitive and EGFR-targeted liposomal systemic delivery of oAd can be a promising strategy to address the conventional limitations of oAd to effectively treat EGFR-positive cancer in a safe manner.

Neonatal SARS-CoV-2 mRNA Vaccination Efficacy Is Influenced by Maternal Antibodies.

Vaccination in pregnancy guards against infection. Maternal antibodies, however, can inhibit antibody production in neonates. We sought to determine the effects of maternal vaccination on neonatal immune response to a SARS-CoV-2 mRNA vaccine. We hypothesized that mRNA-lipid nanoparticles (LNP) vaccination allows for a de novo neonatal antibody response even in the presence of vertically transmitted maternal antibodies. Female mice were vaccinated with SARS-CoV-2 spike receptor binding domain (RBD) mRNA-LNPs. Mice were then bred, and 21-day-old pups were inoculated with the same mRNA-LNPs. Spike-specific IgG ELISAs were performed using mouse serum. A SARS-CoV-2 spike protein peptide library to perform peptide ELISAs characterized high affinity binding domains within the spike protein. Results were analyzed with one-way ANOVAs with Tukey's multiple comparisons tests. Compared to pups of unvaccinated dams, there were high levels of spike-specific IgG detected in the pups of vaccinated dams at 3 weeks of life (p < 0.0001). After neonatal vaccination, pups of unvaccinated dams had higher spike-specific serum IgG than pups of vaccinated dams at 12 weeks of life (p < 0.001). Antibody specificity to peptide moieties within spike RBD were similar when comparing a vaccinated dam to her pup at Week 3 of life, with different binding affinities observed in the pups by Week 15 of life. Pre-existing maternal antibodies may partially blunt the initial neonatal antibody response to mRNA-LNPs vaccination. This vaccine strategy, however, does not prohibit the subsequent development of a broad range of RBD antibody specificities that may be protective.

Intrinsic Proteolytic Activities from Cancer Cells Are Sufficient to Activate Alkoxyamine Prodrugs and Induce Cell Death.

In search of better specificity and lower chances of resistance, protease-activatable alkoxyamine prodrugs to fight cancer have been proposed. These molecules are made of a peptide linked to an alkoxyamine. Proteolysis of the peptide converts the stable prodrug at 37 °C to a metastable alkoxyamine that spontaneously homolyzes into two free radicals: a stable nitroxide and a very reactive alkyl radical. The alkyl radical induces apoptosis in the surrounding cells by inducing random chemical alterations. Here, we show that varying the peptide moiety from succinyl-Ala-Ala-Pro-Val- to PyroGlu-Gly-Arg- or PyroGlu-Gly-Lys- is effective in switching the activating enzyme from elastase to urokinase. Furthermore, these prodrugs induce the death of HT-1080 cells, a cell line that secretes several active proteases in culture. This cytotoxic activity can be suppressed by protease inhibitors and does not affect cell lines devoid of active urokinase. We thus provide examples of alkoxyamine prodrugs that are efficiently activated by the limited intrinsic protease activity and that succeed in the destruction of cancer cell lines and cancer cells from tumor explants.

Exploring the Pharmacological Effects of Bioactive Peptides on Human Nervous Disorders: A Comprehensive Review.

A family of peptides known as bioactive peptides has unique physiological properties and may be used to improve human health and prevent illness. Because bioactive peptides impact the immunological, endocrine, neurological, and cardiovascular systems, they have drawn a lot of interest from researchers. According to recent studies, bioactive peptides have a lot to offer in the treatment of inflammation, neuronal regeneration, localized ischemia, and the blood-brain barrier. It investigates various peptide moieties, including antioxidative properties, immune response modulation, and increased blood-brain barrier permeability. It also looks at how well they work as therapeutic candidates and finds promising peptide-based strategies for better outcomes. Furthermore, it underscores the need for further studies to support their clinical utility and suggests that results from such investigations will enhance our understanding of the pathophysiology of these conditions. In order to understand recent advances in BPs and to plan future research, academic researchers and industrial partners will find this review article to be a helpful resource.

Solid-phase synthesis of amphiphilic cyclic peptides as a surfactin mimetic

The cyclic lipopeptide surfactin, an anionic biosurfactant, has received increased interest owing to its unique characteristics and promising applications. Although surfactin is known to exhibit distinctive surface activities and self-assembly ability, the role of the cyclic peptide moiety in its physico-chemical properties requires further investigation. Here, we report the solid-phase peptide synthesis of surfactin mimics such as cyclic heptapeptides with the same amino acid sequence as surfactin (CSF) and cyclic octapeptides with dodecyl chains (CSF12). The structure–property relationships of the cyclic peptides were then examined. The acidic forms of CSF and CSF12 were poorly soluble in water, but the addition of 1.5 or 2.0 equiv. of NaOH increased their solubility in aqueous solutions. The disodium salt of CSF (CSF-2Na) reduced the surface tension of water to 39.0 mN/m despite its absence of a long alkyl chain, indicating that the cyclic peptide moiety plays a crucial role in the surface activity of the surfactin mimic. In the case of the disodium salt of CSF12 (CSF12–2Na), the introduction of a dodecyl chain to the cyclic peptide moiety led to an increase in molecular orientation such that saturation at the air–water interface was observed. Thus, a long alkyl chain enhances the molecular assembly of the cyclic peptide at the air–water interface. The introduction of a long alkyl chain also enhanced the solubilisation of phospholipids. For instance, CSF12–1.5Na induced the solubilisation of L-α-dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles in phosphate-buffered saline (PBS). These findings greatly contribute to the fundamental understanding of the broad spectrum of physico-chemical properties and biological activities of bio-derived cyclic peptides. Furthermore, these insights can also be helping design libraries for developing cyclic peptides for challenging therapeutics in skin disease or as cosmeceuticals to enhance skin appearance.

Computational 3D Models of Fe2+/3+-Aβ1-42 Complexes Associated with Alzheimer's Disease.

The interaction between iron and amyloid-beta (Aβ) peptides has received significant attention in Alzheimer's disease (AD) research due to its potential implications in developing this pathology. However, the coordination preferences of iron and Aβ1-42 have not been thoroughly investigated or remain unknown. This study employs a computational protocol that combines homology modeling techniques with quantum mechanics (DTF-xTB) calculations to build and evaluate several 3D models of Fe2+/3+-Aβ1-42. Our results reveal well-defined complexes for both the metal and peptide moieties, and we discuss the molecular interactions stabilizing these complexes by elucidating the coordinating environments and binding preferences. These proposed models offer valuable insights into the role of iron in Alzheimer's disease (AD) pathology.

Structural Features Influencing the Bioactive Conformation of Angiotensin II and Angiotensin A: Relationship between Receptor Desensitization, Addiction, and the Blood-Brain Barrier.

The N-terminal portion of the octapeptide angiotensin II (DRVYIHPF; AngII), a vasopressor peptide that favorably binds to, and activates, AngII type 1 receptor (AT1R), has an important role in maintaining bioactive conformation. It involves all three charged groups, namely (i) the N-terminal amino group cation, (ii) the Asp sidechain anion and (iii) the Arg guanidino cation. Neutralization of any one of these three charged groups results in a substantial reduction (<5%) in bioactivity, implicating a specialized function for this cluster. In contrast, angiotensin A (ARVYIHPF; AngA) has reduced bioactivity at AT1R; however, replacement of Asp in AngII with sarcosine (N-methyl-glycine) not only restores bioactivity but increases the activity of agonist, antagonist, and inverse agonist analogues. A bend produced at the N-terminus by the introduction of the secondary amino acid sarcosine is thought to realign the functional groups that chaperone the C-terminal portion of AngII, allowing transfer of the negative charge originating at the C-terminus to be transferred to the Tyr hydroxyl-forming tyrosinate anion, which is required to activate the receptor and desensitizes the receptor (tachyphylaxis). Peptide (sarilesin) and nonpeptide (sartans) moieties, which are long-acting inverse agonists, appear to desensitize the receptor by a mechanism analogous to tachyphylaxis. Sartans/bisartans were found to bind to alpha adrenergic receptors resulting in structure-dependent desensitization or resensitization. These considerations have provided information on the mechanisms of receptor desensitization/tolerance and insights into possible avenues for treating addiction. In this regard sartans, which appear to cross the blood-brain barrier more readily than bisartans, are the preferred drug candidates.

Molecular basis for antibody recognition of multiple drug–peptide/MHC complexes

The HapImmuneTM platform exploits covalent inhibitors as haptens for creating major histocompatibility complex (MHC)-presented tumor-specific neoantigens by design, combining targeted therapies with immunotherapy for the treatment of drug-resistant cancers. A HapImmune antibody, R023, recognizes multiple sotorasib-conjugated KRAS(G12C) peptides presented by different human leukocyte antigens (HLAs). This high specificity to sotorasib, coupled with broad HLA-binding capability, enables such antibodies, when reformatted as T cell engagers, to potently and selectively kill sotorasib-resistant KRAS(G12C) cancer cells expressing different HLAs upon sotorasib treatment. The loosening of HLA restriction could increase the patient population that can benefit from this therapeutic approach. To understand the molecular basis for its unconventional binding capability, we used single-particle cryogenic electron microscopy to determine the structures of R023 bound to multiple sotorasib-peptide conjugates presented by different HLAs. R023 forms a pocket for sotorasib between the VH and VL domains, binds HLAs in an unconventional, angled way, with VL making most contacts with them, and makes few contacts with the peptide moieties. This binding mode enables the antibody to accommodate different hapten-peptide conjugates and to adjust its conformation to different HLAs presenting hapten-peptides. Deep mutational scanning validated the structures and revealed distinct levels of mutation tolerance by sotorasib- and HLA-binding residues. Together, our structural information and sequence landscape analysis reveal key features for achieving MHC-restricted recognition of multiple hapten-peptide antigens, which will inform the development of next-generation therapeutic antibodies.

Engineering peptide drug therapeutics through chemical conjugation and implication in clinics.

The development of peptide drugs has made tremendous progress in the past few decades because of the advancements in modification chemistry and analytical technologies. The novel-designed peptide drugs have been modified through various biochemical methods with improved diagnostic, therapeutic, and drug-delivery strategies. Researchers found it a helping hand to overcome the inherent limitations of peptides and bring continued advancements in their applications. Furthermore, the emergence of peptide-drug conjugates (PDCs)-utilizes target-oriented peptide moieties as a vehicle for cytotoxic payloads via conjugation with cleavable chemical agents, resulting in the key foundation of the new era of targeted peptide drugs. This review summarizes the various classifications of peptide drugs, suitable chemical modification strategies to improve the ADME (adsorption, distribution, metabolism, and excretion) features of peptide drugs, and recent (2015-early 2024) progress/achievements in peptide-based drug delivery systems as well as their fruitful implication in preclinical and clinical studies. Furthermore, we also summarized the brief description of other types of PDCs, including peptide-MOF conjugates and peptide-UCNP conjugates. The principal aim is to provide scattered and diversified knowledge in one place and to help researchers understand the pinching knots in the science of PDC development and progress toward a bright future of novel peptide drugs.

Process and quality evaluation of different improved composts made with a smart laboratory pilot plant

This study monitored the process and investigated the quality of compost obtained from different biomasses. Five blends of agri-food waste were composted by a laboratory pilot plant named COMPOSTER, that is designed to optimize biodegradation, and produce compost efficiently. The COMPOSTER consists of two 35-liter nearly adiabatic, aerated bioreactors that simulate an industrial process involving the typical sequence of mesophilic-thermophilic-mesophilic phases. It continuously monitors and records temperature, internal pressure, and biomass weight, while controlling and quantifying oxygen consumption and carbon dioxide emissions resulting from aerobic biodegradation. All composts were characterized for their main chemical, physical, and molecular features, as well as their suppressiveness against Fusarium oxysporum f.sp. lycopersici (FOL), tested on tomato seedlings. Optimized biodegradation yielded 50–60 % mature compost with a cumulative oxygen consumption ranging from 282 to 456 gO2 per kg of dry matter, with peaks of 2.55 gO2 per kg of volatile solids per hour, and carbon dioxide emissions of 22–36 % of the initial carbon content, with peaks of 5.89 g CO2 per kg of volatile solids per hour. Blends containing more ligno-cellulosic ingredients showed higher yields and lower CO2 emissions. Most of the nitrogen present initially was retained in the final compost; indeed, all mixtures exhibited an apparent nitrogen concentration increase due to carbon loss. Composting determined deep modifications in the molecular structure of the organic matter. 13C CPMAS-NMR and off-line thermochemolysis GC-MS analyses highlighted decomposition degree of polysaccharides and peptidic moieties, selective preservation of aliphatic and aromatic recalcitrant compounds, and optimal ongoing humification. All composts were non-phytotoxic, except for that including pepper crop residues, and all resulted rich in macro- and micro-elements for plant nutrition and proved to be active in controlling FOL disease. Compost comprising 81.2 % tomato crop waste exhibited the best growth performance and pathogen control on tomato. Mature, non-phytotoxic, nutrient-rich, and suppressive composts represent promising by-products that can be successfully recycled in agriculture, including high-value applications, leading to lower use of fertilizers and pesticides.

Pyrene-Modified Cyclic Peptides Detect Cu2+ Ions by Fluorescence in Water

The detection of metal ions is an option for maintaining water quality and diagnosing metal ion-related diseases. In this study, we successfully detected metal ions using fluorescent peptides in water. First, we prepared seven linear (L1–L7) and seven cyclic (C1–C7) peptides containing two pyrenyl (Pyr) units and assessed the response to various metal ions by fluorescence. The results indicated that C1, which contains a hexameric cyclic peptide moiety consisting of Pyr and Gly units, did not show a fluorescent response to metal ions, while the linear L1 corresponding to C1 showed a response to Cu2+, but its selectivity was found to be poor through a competition assay for each metal ion. We then assessed C2–C7 and L2–L7, in which Gly was replaced by His units at various positions in the same manner. The results showed that C2–C7 responded to Cu2+ in a manner dependent on the His position. Additionally, superior selectivity was observed in C7 through a competition assay. These results demonstrate that the structural restriction of peptides and the sequence affect the selective detection of Cu2+ and reveal that peptides with an appropriate structure can accomplish the fluorescent detection of Cu2+ specifically.

Abstract CT188: A Phase I trial of AVA6000, a Fibroblast Activation Protein (FAP)-released and tumor microenvironment (TME)-targeted doxorubicin peptide drug conjugate in patients with FAP-positive solid tumors

Abstract Background: AVA6000 is a peptide drug conjugate, consisting of a peptide moiety that is specifically cleaved by FAP in the TME that is bound to doxorubicin. FAP is selectively overexpressed in many solid tumors. The peptide moiety linker (pre|CISIONTM) prevents cellular entry of doxorubicin unless cleaved by FAP, thus enabling targeted delivery of doxorubicin to tumors. Design: The safety, PK and preliminary efficacy of AVA6000 was studied in a first-in-man, multicenter dose escalation phase I trial. AVA6000 was administered intravenously q3w using a standard 3+3 design in patients with locally advanced or metastatic solid tumors reported to be FAP-positive. PK (AUC) based dosing was implemented to calculate maximum cycles of AVA6000 with the cumulative limit of 550 mg/m2. Results: Forty patients (median age 65 years, range 30-79), with median 3 prior lines of therapy (range, 0-7) received escalating AVA6000 doses from 80mg/m2 (51 mg/m2 doxorubicin; molar equivalent, 0.675) to 385 mg/m2 (260 mg/m2 doxorubicin equivalent). Tumor types included soft tissue sarcoma (30%), colorectal cancer (27.5%), pancreatic cancer (20%), cancers of the biliary tract (7.5%). The safety profile was favorable, the most frequent adverse events (any grade) being fatigue (50%), alopecia (42.5%), and nausea (32.5%), with rare grade 3-4 hematologic toxicities of neutropenia (7.5%), anemia, thrombocytopenia, and WBC decreased (5% each). Grade 3 non-hematologic toxicities included mucositis, fatigue and hematemesis (n=1 each). No grade 4 non-hematologic toxicities were reported. Two DLTs were observed of grade 2 cardiac failure (120 mg/m2; LVEF decrease 61 to 39%) and grade 4 neutropenia/thrombocytopenia (200 mg/m2). AVA6000 distributes rapidly with a t1/2 of 45 min. The Cmax of released doxorubicin was reduced as compared to standard dose doxorubicin (range 78-93% reduction) across dose cohorts. Tumor biopsy data demonstrate concentration of doxorubicin in the TME of mean 860 ng/gm (range 76-2310 ng/gm, n=9). In contrast, blood samples taken with the biopsy demonstrate a circulating free doxorubicin of 8.3 ng/ml (range 2.4-15.9), indicating concentration of doxorubicin in the tumor relative to plasma. Using RECISTv.1.1, one PR (-65%) with duration of 6 months was observed in a patient with undifferentiated pleomorphic sarcoma at 160 mg/m2, and a mixed response in a patient with angiosarcoma (SLD -22%) at 200 mg/m2. The disease control rate was 50%, at 12 wks. In each case, SD &amp;gt; 4 months or PR was associated with high FAP enzyme activity in the on-study tumor biopsy compared to observed disease progression as best response (n=6). Conclusions: AVA6000 delivers high concentration of doxorubicin to the TME relative to plasma which results in antitumor activity in tumors with high FAP activity. A q2w dose escalation arm is ongoing. Citation Format: Udai Banerji, Natalie Cook, Alan Anthoney, Ruth Plummer, William D. Tap, Jeffry T. Evans, Lee D. Cranmer, Christopher Plummer, Paul Loadman, Gezim Lahu, Huw S. Jones, Nelson Kinnersley, Fiona McLaughlin, Chris Twelves. A Phase I trial of AVA6000, a Fibroblast Activation Protein (FAP)-released and tumor microenvironment (TME)-targeted doxorubicin peptide drug conjugate in patients with FAP-positive solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT188.

Abstract 6579: DS-3939a, a novel TA-MUC1-targeting antibody-drug conjugate (ADC) with a DNA topoisomerase I inhibitor DXd, exhibits potent antitumor activity in preclinical models

Abstract Background: Tumor-associated mucin-1 (TA-MUC1) is a tumor-specific transmembrane glycoprotein with aberrant glycosylation. It is highly expressed in various human epithelial cancers, making it an attractive target for cancer therapy. DS-3939a is a TA-MUC1 targeting antibody-drug conjugate (ADC) structurally composed of a humanized anti-TA-MUC1 antibody, an enzymatically cleavable tetrapeptide-based linker, and a DNA topoisomerase I inhibitor (DXd) with a high drug-to-antibody ratio (DAR). In this study, the pharmacological activity of DS-3939a was evaluated using preclinical in vitro and in vivo models. Methods: TA-MUC1 expression was assessed by immunohistochemistry and flow cytometry. Binding specificity of DS-3939a was confirmed by enzyme-linked immunosorbent assay. Induction of DNA damage and apoptosis to cancer cells by DS-3939a treatment were detected by Simple Western System. In vitro cell growth inhibitory and in vivo antitumor activities of DS-3939a were evaluated using various cancer cell lines and patient-derived xenograft (PDX) models. Results: Many specimens across multiple cancer types showed positive staining for TA-MUC1, with a particularly high positive rate observed in bladder, lung, and breast cancers. DS-3939a specifically bound to aberrantly glycosylated MUC1 peptides by recognizing both the glycan and backbone peptide moiety of MUC1. In vitro, DS-3939a inhibited the growth of TA-MUC1-positive cancer cells but not of TA-MUC1-negative cancer cells. Neither a parental anti-TA-MUC1 antibody nor isotype control ADC inhibited the growth of these cells. In addition, treatment with DS-3939a and DXd alone induced DNA damage and apoptosis in cancer cells. These results demonstrate that DS-3939a exhibits TA-MUC1-dependent cell growth inhibition through DXd-mediated cytotoxic effect. Moreover, DS-3939a exhibited significant antitumor effects in the several TA-MUC1-positive cancer cell line-derived xenograft models and various PDX models. DS-3939a also induced strong tumor regression even after treatment of other cytotoxic ADCs in several xenograft models. Conclusion: Based on these preclinical results, DS-3939a could provide valuable therapy with potential benefits for patients with TA-MUC1-expressing tumors. A first-in-human phase 1/2 study in patients with advanced solid tumors is currently in progress (NCT05875168). Citation Format: Mayuko Yukiura, Kohei Takano, Kazuki Takahashi, Akiko Zembutsu, Michiko Kitamura, Yoshinobu Shiose, Kokichi Honda, Kazunori Oyama, Wataru Obuchi, Makiko Yamada, Riki Goto, Ken Sakurai, Kazuyoshi Kumagai, Takashi Kagari, Yuki Abe, Toshinori Agatsuma. DS-3939a, a novel TA-MUC1-targeting antibody-drug conjugate (ADC) with a DNA topoisomerase I inhibitor DXd, exhibits potent antitumor activity in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6579.

Regulating interparticle proximity in plasmonic nanosphere aggregates to enhance photoacoustic response and photothermal stability.

Designing plasmonic nanoparticles for biomedical photoacoustic (PA) imaging involves tailoring material properties at the nanometer scale. A key in developing plasmonic PA contrast nanoagents is to engineer their enhanced optical responses in the near-infrared wavelength range, as well as heat transfer properties and photostability. This study introduces anisotropic plasmonic nanosphere aggregates with close interparticle proximity as photostable and efficient contrast agent for PA imaging. Silver (Ag), among plasmonic metals, is particularly attractive due to its strongest optical response and highest heat conductivity. Our results demonstrate that close interparticle proximity in silver nanoaggregates (AgNAs), spatially confined within a polymer shell layer, leads to blackbody-like optical absorption, resulting in robust PA signals through efficient pulsed heat generation and transfer. Additionally, our AgNAs exhibit a high photodamage threshold highlighting their potential to outperform conventional plasmonic contrast agents for high-contrast PA imaging over multiple imaging sessions. Furthermore, we demonstrate the capability of the AgNAs for molecular PA cancer imaging in vivo by incorporating a tumor-targeting peptide moiety.

Peptide-Drug Conjugates: Design, Chemistry, and Drug Delivery System as a Novel Cancer Theranostic.

The emergence of peptide-drug conjugates (PDCs) that utilize target-oriented peptide moieties as carriers of cytotoxic payloads, interconnected with various cleavable/noncleavable linkers, resulted in the key-foundation of the new era of targeted therapeutics. They are capable of retaining the integrity of conjugates in the blood circulatory system as well as releasing the drugs at the tumor microenvironment. Other valuable advantages are specificity and selectivity toward targeted-receptors, higher penetration ability, and drug-loading capacity, making them a suitable candidate to play their vital role as promising carrier agents. In this review, we summarized the types of cell-targeting (CTPs) and cell-penetrating peptides (CPPs) that have broad applications in the advancement of targeted drug-delivery systems (DDS). Moreover, the techniques to overcome the limitations of peptide-chemistry for their extensive implementation to construct the PDCs. Besides this, the diversified breakthrough of linker chemistry, and ample knowledge of various cytotoxic payloads used in PDCs in recent years, as well as the mechanism of action of PDCs was critically discussed. The principal aim is to provide scattered and diversified knowledge in one place and to help researchers understand the pinching knots in the science of PDC development, also their progression toward a bright future for PDCs as novel theranostics in clinical practice.

Synthesis and Evaluation of Novel 99mTc-Labeled FGFR2-Targeting Peptides.

To develop radiolabeled FGFR2-targeting probes for visualizing fibroblast growth factor receptor (FGFR) expression levels in the tumor microenvironment, four novel 99mTc-labeled FGFR2-targeting peptides ([99mTc]Tc-FGFR2-1, [99mTc]Tc-FGFR2-2, [99mTc]Tc-FGFR2-3, and [99mTc]Tc-FGFR2-4) with different amino acid linkers between the targeted peptide moiety and the 99mTc chelating group were designed and synthesized. The in vitro cellular inhibition, internalization, and efflux results demonstrated that the four 99mTc complexes exhibited FGFR2-specific binding and prolonged cellular retention in DU145 human prostate cancer cells, which indicated that modification from the glycine side (N-terminal) of CH02 was feasible. Among them, [99mTc]Tc-FGFR2-1 exhibited the highest in vitro cellular uptake and in vivo tumor uptake at 30 min postinjection, and tumor uptake could be significantly inhibited by the competitor CH02 (53% inhibited, p < 0.05), suggesting the tumor-specific targeting ability of [99mTc]Tc-FGFR2-1. The DU145-xenografted tumor lesions were clearly visualized by single photon emission computed tomography (SPECT)/CT at 30 min postinjection of [99mTc]Tc-FGFR2-1, highlighting its potential as a SPECT imaging probe for tumor FGFR2 detection.

Total substitution and partial modification of the set of non-ribosomal peptide synthetases clusters lead to pyoverdine diversity in the Pseudomonas fluorescens complex.

Pyoverdines are high affinity siderophores produced by most Pseudomonas with a wide role in microbial interspecies interactions. They are primarily composed of a conserved chromophore moiety, an acyl side chain and a peptide backbone which may be highly variable among strains. Upon ferric iron sequestration, pyoverdines are internalized through specialized receptors. The peptide precursor of pyoverdine, termed ferribactin, is synthesized by a set of non-ribosomal peptide synthetase (NRPS) enzymes and further modified by tailoring enzymes. While PvdL, the NRPS responsible for the synthesis of the peptide moiety that derives into the chromophore is conserved, the NRPSs for the peptide backbone are different across fluorescent Pseudomonas. Although the variation of pyoverdine is a widely recognized characteristic within the genus, the evolutionary events associated with the diversity and distribution of this trait remain mostly unknown. This study analyzed the NRPSs clusters for the biosynthesis of the peptide backbone of ferribactin in the genomes of a representative subset of strains of the Pseudomonas fluorescens complex. Bioinformatic analysis of the specificity of adenylation domains of the NRPSs allowed the prediction of 30 different pyoverdine variants. Phylogenetic reconstruction and mapping of the NRPS clusters pinpointed two different general levels of modifications. In the first level, a complete replacement of the set of NRPRs by horizontal transfer occurs. In the second level, the original set of NRPSs is modified through different mechanisms, including partial substitution of the NRPS genes by horizontal transfer, adenylation domain specificity change or NRPS accessory domain gain/loss.

Near-Infrared Chemiluminescence Imaging of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) has a high prevalence but is poorly managed for cancer patients due to the lack of reliable and sensitive diagnostic techniques. Molecular optical imaging can provide a noninvasive way for real-time monitoring of CIPN; However, this is not reported, likely due to the absence of optical probes capable of imaging deep into the spinal canal and possessing sufficient sensitivity for minimal dosage through local injection into the dorsal root ganglia. Herein, a near-infrared (NIR) chemiluminophore (MPBD) with a chemiluminescence quantum yield higher than other reported probes is synthesized and a NIR activatable chemiluminescent probe (CalCL) is developed for in vivo imaging of CIPN. CalCL is constructed by caging MPBD with calpain-cleavable peptide moiety while conjugating polyethylene glycol chain to endow water solubility. Due to the deep-tissue penetration of chemiluminescence and specific turn-on response of CalCL toward calpain (a hallmark of CIPN), it allows for sensitive detection of paclitaxel-mediated CIPN in living mice, which is unattainable by fluorescence imaging. This study thus not only develops a highly efficient chemiluminescent probe, but also presents the first optical imaging approach toward high-throughput screening of neurotoxic drugs.

Optimization of the Antibacterial Spectrum and the Developability Profile of the Novel-Class Natural Product Corramycin.

Corramycin 1 is a novel zwitterionic antibacterial peptide isolated from a culture of the myxobacterium Corallococcus coralloides. Though Corramycin displayed a narrow spectrum and modest MICs against sensitive bacteria, its ADMET and physchem profile as well as its high tolerability in mice along with an outstanding in vivo efficacy in an Escherichia coli septicemia mouse model were promising and prompted us to embark on an optimization program aiming at enlarging the spectrum and at increasing the antibacterial activities by modulating membrane permeability. Scanning the peptidic moiety by the Ala-scan strategy followed by key stabilization and introduction of groups such as a primary amine or siderophore allowed us to enlarge the spectrum and increase the overall developability profile. The optimized Corramycin 28 showed an improved mouse IV PK and a broader spectrum with high potency against key Gram-negative bacteria that translated into excellent efficacy in several in vivo mouse infection models.

Synthesis, Hydrolytic Stability and In Vivo Biological Study of Bioconjugates of the Tetrapeptides FELL Containing Pyrrole Moiety.

Bioconjugates are promising alternatives for the multiple targeting of any disease. Pyrrole heterocycle is well known with many activities and is a building block of a lot of medical drugs. On the other hand, peptides are short molecules with many advantages such as small size, ability to penetrate the cell membrane and bond-specific receptors, vectorizing potential, etc. Thus, hybrid molecules between peptide and pyrrole moiety could be a promising alternative as an anti-pain tool. New bioconjugates with a general formula Pyrrole (α-/β-acid)-FELL-OH (NH2) were synthesized using Fmoc/OtBu peptide synthesis on solid support. HPLC was used to monitor the purity of newly synthesized bioconjugates. Their structures were proven by electrospray ionization mass spectrometry. The Paw Pressure test (Randall-Selitto test) was used to examinate the analgesic activity. Hydrolytic stability of targeted structures was monitored in three model systems with pH 2.0, 7.4 and 9.0, including specific enzymes by means of the HPLC-UV method. The obtained results reveal that all newly synthesized bioconjugates have analgesic activity according to the used test but free pyrrole acids have the best analgesic activity. Although free pyrrole acids showed the best analgesic activity, they are the most unstable for hydrolysis. Combination with peptide structure leads to the hydrolytic stabilization of the bioconjugates, albeit with slightly reduced activity.