Soluble Peptides Research Articles

The antioxidant activity of protein fractions from Sacha inchi seeds after a simulated gastrointestinal digestion

Defatted Sacha inchi seed is an important source of protein (up to 59.1% dry weight). Besides, the application of antioxidant peptides is often limited due to a reduction in their activities by enzymatic hydrolysis during gastrointestinal digestion. Therefore, the objective of this study was to obtain stable, anti-digestive and strongly antioxidative protein hydrolysates against non-communicable diseases (NCDs) by investigating the changes in the antioxidant capacities of the protein fractions (albumin, globulin and glutelin) from Sacha inchi seeds (PFFSIS) during simulated gastrointestinal digestion (SGID). The results showed SGID promoted the release of smaller bioactive peptides from PFFSIS evidenced by the increased soluble peptide content, DH and low MW distribution. Besides, the extracellular antioxidant capacity (ABTS•+ radical-scavenging activity, reducing power and ORAC value) and intracellular antioxidant capacity (inhibiting erythrocyte hemolysis by enzyme system (SOD, CAT and GSH-Px) and non-enzyme substances (GSH)) of PFFSIS were significantly increased after the SGID due to potential antioxidant mechanisms inside and outside the cell. The glutelin fraction showed the highest antioxidant activity after the SGID, followed by albumin and globulin fractions. These results highlight the potential application of glutelin fraction hydrolysates of Sacha inchi seeds as natural antioxidant supplements to prevent NCDs.

Characterization of fermented soymilk by Schleiferilactobacillus harbinensis M1, based on the whole-genome sequence and corresponding phenotypes

The use of Schleiferilactobacillus (S.) harbinensis M1 as a starter culture, has been shown to improve the organoleptic quality of fermented soymilk, but its contribution to nutrient transformation and health-related functionality remains unclear. This study characterized the biotransformation of carbohydrates, isoflavones, proteins and free amino acids, as well as the antioxidant and antiproliferative activities of soymilk fermented by S. harbinensis M1. After fermentation, soybean carbohydrates were mainly converted into lactic acid (76.68 mmol/L) and acetic acid (8.19 mmol/L), isoflavone glucosides (daidzin and genistin) were partially converted to aglycones (daidzein and genistein). Soybean proteins were extensively hydrolyzed into oligopeptides and free amino acids, and the soluble peptide fraction (451-189 Da) increased from 4.6% to 86%. Whole-genome sequencing of S. harbinensis M1 revealed a 3,592,195 bp circular chromosome with 53.02% (G + C) content and 3375 coding genes. Metabolic prediction revealed the enzymes required for carbohydrate/pyruvate metabolism and isoflavone biotransformation. The whole proteolytic system was predicted, including peptide transport system and 66 genes encoding proteinases/peptidases. S. harbinensis M1 significantly (p < 0.05) improved the antioxidant activity and antiproliferative effects of soymilk against HepG2/MCF-7 cells. These findings suggest that S. harbinensis M1 can be used as a proteolytic starter-culture to make functional fermented foods.

Soluble fms-like tyrosine kinase-1 and angiotensin2 target calcitonin gene-related peptide family peptides in maternal vascular smooth muscle cells in pregnancy†.

Peptide function was assessed by Cyclic adenosine monophosphate (cAMP) assays and wire myograph; mRNA expression by Polymerase chain reaction (PCR) and protein-protein interaction by proximity ligation assay and co-immunoprecipitation. All three peptides increased cAMP synthesis in the order of efficacy CALCB > ADM = ADM2 and vascular endothelial growth factor (VEGF) mRNA in OASMC (P < 0.05); sFLT-1 mediated decrease in cAMP synthesis (P < 0.05) is differentially rescued by all three CALCB family peptides in OASMC (P < 0.005); sFLT-1 decreased receptor activity-modifying protein (RAMP)1 and RAMP2 mRNA expression (P < 0.05); Ang2 decreased the expression of calcitonin-receptor-like receptor and RAMP1 mRNA and desensitized CALCB and ADM2 receptors in OASMC (P < 0.05); sFLT-1 increased RAMP1and Ang2 type 1 receptor (AT1R) interaction in OASMC which is inhibited in presence of all three peptides; and all three peptides relax OA in PE with enhanced ADM2 response (P < 0.05). sFLT-1 and Ang2 impair OASMC mediated functional responses of CALCB family peptides which can be inhibited by respective peptide treatment. The sensitivity of OA for CALCB, ADM, and ADM2-mediated relaxation is retained in PE.

Retinoid X receptor activation promotes re-myelination in a very old triple transgenic mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is the main cause of dementia in the world. Studies of human AD brains show abnormalities in the white matter and reduction of myelin and oligodendrocyte markers. It has been proposed that oligodendrocyte progenitor cells (OPCs) present in the adult brain are a potential source for re-myelination, through proliferation and differentiation into mature oligodendrocytes. Bexarotene, a Retinoid X Receptor agonist, has been demonstrated to reverse behavioral deficits and to improved synaptic transmission and plasticity in murine models of AD, which was associated with the reduction of soluble Aβ peptides. In the present study, we analyzed changes in the expression of oligodendrocyte lineage markers following oral administration of Bexarotene in a very old (24-month-old) triple transgenic mouse model of AD (3xTg-AD), for which early demyelination changes have been previously described. Bexarotene increased the expression of OPCs and intermediate oligodendrocyte progenitors (Olig2+ and O4+), and increased the number of mitotic (O4+) and myelinating mature (MBP+) oligodendrocytes. We clearly show that Bexarotene promotes re-myelination which might be important for the previously observed cognitive improvement of 3xTg-AD mice treated with this drug.

Coronary stent CD31-mimetic coating favours endothelialization and reduces local inflammation and neointimal development in vivo.

AimsThe rapid endothelialization of bare metal stents (BMS) is counterbalanced by inflammation-induced neointimal growth. Drug-eluting stents (DES) prevent leukocyte activation but impair endothelialization, delaying effective device integration into arterial walls. Previously, we have shown that engaging the vascular CD31 co-receptor is crucial for endothelial and leukocyte homeostasis and arterial healing. Furthermore, we have shown that a soluble synthetic peptide (known as P8RI) acts like a CD31 agonist. The aim of this study was to evaluate the effect of CD31-mimetic metal stent coating on the in vitro adherence of endothelial cells (ECs) and blood elements and the in vivo strut coverage and neointimal growth.Methods and resultsWe produced Cobalt Chromium discs and stents coated with a CD31-mimetic peptide through two procedures, plasma amination or dip-coating, both yielding comparable results. We found that CD31-mimetic discs significantly reduced the extent of primary human coronary artery EC and blood platelet/leukocyte activation in vitro. In vivo, CD31-mimetic stent properties were compared with those of DES and BMS by coronarography and microscopy at 7 and 28 days post-implantation in pig coronary arteries (n = 9 stents/group/timepoint). Seven days post-implantation, only CD31-mimetic struts were fully endothelialized with no activated platelets/leukocytes. At day 28, neointima development over CD31-mimetic stents was significantly reduced compared to BMS, appearing as a normal arterial media with the absence of thrombosis contrary to DES.ConclusionCD31-mimetic coating favours vascular homeostasis and arterial wall healing, preventing in-stent stenosis and thrombosis. Hence, such coatings seem to improve the metal stent biocompatibility.

Study on the Effect and Mechanism of Paclitaxel-Succini Acid Drug-Loaded Nanofibers in Treating Lung Cancer.

In recent years, nanotechnology has made great progress in the development and application of tumor detection, diagnosis, and treatment, and eventually formed a "tumor nanomedicine." The emerging field of "materials." Nanoparticles have attracted much attention because they can overcome physiological barriers, effectively deliver hydrophobic drugs, and specifically target tumor tissues. At present, nanomedicines mainly include lipid nanoparticles, polymer nanoparticles granules, gold nanoparticles, magnetic nanoparticles, mesoporous silica, and other dosage forms. The use of nanomaterials as carriers in the treatment of lung cancer has unique advantages in achieving targeted drug delivery, slow-release drugs, and improvement of poorly soluble drugs and peptide drugs show obvious advantages in terms of bioavailability and reduction of adverse reactions, and have broad research and development prospects. This paper reports a new type of self-assembled Ptx-SA drug-loaded nanometers based on the carrier-free concept fiber, and it was found that the drug-loaded fiber has better cellophilicity, anti-tumor effect in vitro and in vivo than naked drug, and may be mediated by regulating the expression of related proteins. Therefore, the paclitaxel-loaded nano drug delivery system serves as a new type of nano preparation for treating lung cancer is worth further research.

Effect of glycation degree on the in vitro simulated gastrointestinal digestion: A promising formulation for egg white gel with controlled digestibility

The mechanism between food gelation and its digestibility has attracted increasing attention over the past few decades. This study aimed to evaluate the effect of glycation degree on the gelation and digestibility of egg white gel (EWG) using an in vitro model and a multi-scale characterization of gel structure. Results showed that EWG glycated with increasing d-ribose by covalent bonds exhibited better gelling properties and lower in vitro digestibility according to the appearance of soluble proteins and peptides. Besides, glycation preference for ovotransferrin at lysine might be important for regulating gel structure and proteolysis accessibility via the ratio of fibrous and granular aggregates. Moreover, gel structure was predominant over amino acids modification for digestibility. Binding disorder and steric hindrance could ascribe to the lower digestibility of gels. These findings are enlightening for the formulation and production of food matrix with controlled digestibility through glycation in food and related pharmaceutical fields.

Changes in flavor compounds of Aloididae aloidi during enzymatic hydrolysis

Protamex was selected to prepare the hydrolysate. E-tongue, free amino acid combined with soluble peptide analysis were used to detect the flavor changes of Aloididae aloidi during enzymolysis. Degree of proteolysis increased with the prolongation of enzymolysis time, and reached the maximum value at 8 hours. The content of soluble peptide of hydrolysate increased firstly and then decreased in the later process. The E-tongue could effectively distinguish the taste difference of hydrolysates at different enzymolysis time, and the hydrolysate presented strong bitterness and astringency during the whole enzymolysis. The total amount of free amino acids in the hydrolysate increased gradually, and some sweet, umami and bitter amino acids increased in varying degrees during the process of enzymolysis.

Antimicrobial and pro-angiogenic properties of soluble and nanoparticle-immobilized LL37 peptides.

Antimicrobial peptides (AMPs), such as LL37 peptides, may be immobilized on the surface of medical devices to render them with antimicrobial and angiogenic properties. However, little is known about LL37 properties after immobilization. Here, we have studied the antimicrobial and pro-angiogenic activity of soluble and immobilized LL37 peptides (conjugated to gold nanoparticles). Both soluble and immobilized LL37 peptides have potent antimicrobial activity against Gram-positive and Gram-negative bacteria in the presence of 10% human serum (HS). However, the immobilized LL37 peptides showed less cytotoxicity to endothelial cells (ECs) at a concentration that was able to kill bacteria. Interestingly, although both soluble and immobilized LL37 peptides showed pro-angiogenic activities in Matrigel and chorioallantoic membrane (CAM) assays, they induce different signalling pathways in ECs. The results described here highlight the importance of investigating the properties of immobilized AMPs that might act as a new entity.

Combined ultrasound and heat pretreatment improve the enzymatic hydrolysis of clam (Aloididae aloidi) and the flavor of hydrolysates

The effects of pretreatments with ultrasound (UP), heat (HP), and combinations of heat-ultrasound (HP-UP) and ultrasound-heat (UP-HP) on the flesh enzymolysis of clam (Aloididae aloidi) and the flavor characteristics of hydrolysates were investigated. The optimum UP pretreatment conditions for the hydrolysis were obtained at ultrasound power of 500 W, ultrasound time of 20 min, and liquid/solid (L/S) ratio of 2:1 (v/w), yielded 41.33% of hydrolysis degree (DH). Among the different pretreatments, the UP pretreatment had the highest DH value, while the HP-UP pretreatment obtained the highest soluble peptide content. The UP pretreatment efficiently enhanced the contents of taste-active components, including free amino acids, 5′-nucleotides, and succinic acid. The HP pretreatment promoted the formation of pleasant volatile compounds and reduced the content of unpleasant volatile compounds, such as 1-octen-3-ol and 2-ethyl-1-hexanol. The combined HP-UP pretreatment was an effective method for improving the enzymatic hydrolysis of clam and the flavor of hydrolysate.

Progastrin production transitions from Bmi1+/Prox1+ to Lgr5high cells during early intestinal tumorigenesis

Progastrin is an unprocessed soluble peptide precursor with a well-described tumor-promoting role in colorectal cancer. It is expressed at small levels in the healthy intestinal mucosa, and its expression is enhanced at early stages of intestinal tumor development, with high levels of this peptide in hyperplastic intestinal polyps being associated with poor neoplasm-free survival in patients. Yet, the precise type of progastrin-producing cells in the healthy intestinal mucosa and in early adenomas remains unclear. Here, we used a combination of immunostaining, RNAscope labelling and retrospective analysis of single cell RNAseq results to demonstrate that progastrin is produced within intestinal crypts by a subset of Bmi1+/Prox1+/LGR5low endocrine cells, previously shown to act as replacement stem cells in case of mucosal injury. In contrast, our findings indicate that intestinal stem cells, specified by expression of the Wnt signaling target LGR5, become the main source of progastrin production in early mouse and human intestinal adenomas. Collectively our results suggest that the previously identified feed-forward mechanisms between progastrin and Wnt signaling is a hallmark of early neoplastic transformation in mouse and human colonic adenomas.

Impact of 3 Dimensional (3D) Printing in Pharmaceutical Sciences

In the past few years, 3D technology becomes an important component of the locomotive and automobile industry. But, in the field of pharmaceutical sciences, it is quiet new and innovative technology and now getting more attention of the pharmaceutical industries. The article is divided into two parts. The first part incorporates the 3D printing base technologies while the second part of the article focuses on the applications of 3D printing in the pharmaceutical field which includes polypills, gastro retentive dosage form, orodispersable tables, implants. In the past few years, even the USFDA approves and appreciates the use of 3D printing in the pharmaceutical field. The 3D printing in pharmaceutical sciences has the capability to cause a revolution in the health care system. The main purpose of incorporation of 3D printing in pharmaceutical sciences is the development of patient oriented dosage forms.3D printing can be used to solve the problems related to poorly soluble drugs, peptides, potent drugs and release of drugs. Advancement in 3D printing can solve the problems related to the drug delivery system. From the industrial point of view, 3D printing can be cost effective, enhances productivity and manufacturing. Here, we provide the overview and applications of 3D printing in pharmaceutical sciences.

Arthroderma tuberculatum and Arthroderma multifidum Isolated from Soils in Rook (Corvus frugilegus) Colonies as Producers of Keratinolytic Enzymes and Mineral Forms of N and S.

Keratinolytic fungi representing the genus Arthroderma that were isolated from the soils of a rook (Corvus frugilegus) colony were used as biological agents for the disposal of waste feathers. The aim of this study was to assess the abilities of Arthroderma tuberculatum and Arthroderma multifidum fungi with a varied inflow of keratin matter to biodegrade waste feathers. The evaluation was based on the determination of feather mass loss, the activity of keratinolytic enzymes, and the content of mineral N and S forms. It was found that the activity of protease released by the fungi contributed to an increase in the level of soluble proteins and peptides and the concentration of ammonium ions, as well as alkalization of the culture medium. Keratinase activity was significantly correlated with sulfate release, especially in A. tuberculatum cultures. The strains of A. tuberculatum fungi isolated from the soil with the highest supply of organic matter, i.e., strains III, IV, and V, had the lowest enzymatic activity, compared to the A. multifidum strains, but they released mineral nitrogen and sulfur forms that are highly important for fertilization, as well as nutritionally important peptides and amino acids. A. tuberculatum strains can be used for the management of waste feathers that can be applied in agricultural practice.

Characterization of monomeric and soluble aggregated Aβ in Down’s syndrome and Alzheimer’s disease brains

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia and is characterized by the two hallmarks, amyloid plaques and neurofibrillary tangles in the brain. The plaques consist of aggregated beta amyloid (Aβ) peptides, formed by proteolytic cleavages of amyloid precursor protein (APP). Down’s syndrome (DS) is a genetic disease with an extra copy of chromosome 21, harbouring the APP gene. DS individuals are at increased risk to develop amyloid pathology. Most DS have substantial amyloid pathology at their 40s, with clinical signs of deterioration before the age of 60. Our aim was to compare the Aβ peptide pattern in DS and AD brains, to better understand the difference between them.MethodsImmunoprecipitation (IP) in combination with mass spectrometry was used to identify both soluble and insoluble Aβ peptides, as well as to characterise the composition of Aβ oligomers/protofibrils. Two different antibody combinations were used; 6E10+4G8 to identify total Aβ peptide contents and the Aβ protofibril selective antibody mAb158 to identify the Aβ peptides present in oligomers/protofibrils. Before IP, cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (TBS soluble) and formic acid (insoluble) fractions.ResultsFrom IP with 6E10+4G8 several truncated Aβ peptides were identified in all groups, including: 1‐X, 2‐X, 3‐X, 4‐X, 5‐X, 11‐X and –X to 15 as well as post‐translationally modified peptides with oxidation and pyroglutamation. Similarities were observed when comparing the Aβ peptide processing in AD and DS, with the exception of –X to 15 Aβ peptides for which the pattern is different. By using mAb158, Aβ1‐40, Aβ1‐42 and Aβ4‐42 were identified. Higher relative AβX‐42 signals were obtained compared to samples IP’d with 6E10+4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at aa42.ConclusionAll Aβ peptides found in AD are also present in DS (with amyloid pathology) indicating a generally similar pathway of Aβ peptide production, apart from –X to 15. Likewise, the Aβ peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility to exploit the potential utility of a treatment with clinical benefit in sporadic AD for subjects with DS.

In Vitro Effects of (+)MK-801 (dizocilpine) and Memantine on β-Amyloid Peptides Linked to Alzheimer's Disease.

An in vitro effect of (+)MK-801 (dizocilpine), an inhibitor of the glutamate/NMDA and nicotinic acetylcholine receptors, on the Aβ[1-42] and Aβ[1-40] peptides is described and compared to that of memantine. Memantine has been approved by the U.S. Food and Drug Administration for the treatment of mild-moderate Alzheimer's disease. Both compounds accelerated the formation of a β-sheet structure by Aβ[1-42], (+)MK-801 more rapidly than memantine, as observed in a thioflavin T fluorescence assay. The acceleration was followed by a decrease in the fluorescence signal that was not observed when the ligand was absent. Nuclear magnetic resonance spectra of the soluble peptides in the presence and absence of (+)MK-801 demonstrated that the monomeric form did not bind (+)MK-801 and that in the presence of (+)MK-801 the concentration of the monomeric form progressively decreased. Small angle X-ray scattering confirmed that the presence of (+)MK-801 resulted in a more rapid and characteristic transition to an insoluble form. These results suggest that (+)MK-801 and memantine accelerate the transition of Aβ[1-42] and Aβ[1-40] to ThT-negative insoluble forms.

Optimization of Liposomes for Antigen Targeting to Splenic CD169+ Macrophages.

Despite promising progress in cancer vaccination, therapeutic effectiveness is often insufficient. Cancer vaccine effectiveness could be enhanced by targeting vaccine antigens to antigen-presenting cells, thereby increasing T-cell activation. CD169-expressing splenic macrophages efficiently capture particulate antigens from the blood and transfer these antigens to dendritic cells for the activation of CD8+ T cells. In this study, we incorporated a physiological ligand for CD169, the ganglioside GM3, into liposomes to enhance liposome uptake by CD169+ macrophages. We assessed how variation in the amount of GM3, surface-attached PEG and liposomal size affected the binding to, and uptake by, CD169+ macrophages in vitro and in vivo. As a proof of concept, we prepared GM3-targeted liposomes containing a long synthetic ovalbumin peptide and tested the capacity of these liposomes to induce CD8+ and CD4+ T-cell responses compared to control liposomes or soluble peptide. The data indicate that the delivery of liposomes to splenic CD169+ macrophages can be optimized by the selection of liposomal constituents and liposomal size. Moreover, optimized GM3-mediated liposomal targeting to CD169+ macrophages induces potent immune responses and therefore presents as an interesting delivery strategy for cancer vaccination.

Effect of solid-state fermentation with Bacillus subtilis lwo on the proteolysis and the antioxidative properties of chickpeas

In this study, the solid-state fermentation (SSF) of chickpeas by using Bacillus subtilis lwo was performed to evaluate the effect of fermentation on the proteolysis and the antioxidative properties of chickpeas. The soluble protein, peptide, and free amino nitrogen contents; proteinase activity; degradation of protein; peptide profiles; and the antioxidant activities during fermentation were investigated. Results indicated that during the fermentation process, increasing the protease activity resulted in increased release of soluble proteins, peptides, and free amino nitrogen (FAN), which reached their maximum values (15.4 mg/g, 25.8 mg/g, and 1.03 g/100 g, respectively) at 48 h of fermentation. The electrophoretic profiles indicated that most chickpea proteins were degraded after fermentation for 24 h. High-performance liquid chromatography (HPLC) indicated a decreased/disappearance of hydrophobic/large peptides and increased hydrophilic/small peptides. Moreover, the fermented chickpeas showed higher 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical scavenging activities than the unfermented chickpeas. These data suggested that the fermentation process by using B. subtilis lwo improved the proteolysis and the antioxidative activities of chickpeas. Thus, this method may provide a novel way to enhance the value of chickpeas, and the chickpeas fermented by B. subtilis lwo can be used in food industries.

Potential Role of Phosphoglycerol Dihydroceramide Produced by Periodontal Pathogen Porphyromonas gingivalis in the Pathogenesis of Alzheimer's Disease.

BackgroundAmong different types of sphingolipids produced by human cells, the possible engagement of ceramide species in the pathogenesis of Alzheimer’s disease (AD) has attracted recent attention. While ceramides are primarily generated by de novo synthesis in mammalian cells, only a limited number of bacterial species, produce ceramides, including phosphoglycerol dihydroceramide (PGDHC) that is produced by the key periodontal pathogen Porphyromonas gingivalis. Emerging evidence indicates that virulence factors produced by P. gingivalis, such as lipopolysaccharide and gingipain, may be engaged in the initiation and/or progression of AD. However, the potential role of PGDHC in the pathogenesis of AD remains unknown. Therefore, the aim of this study was to evaluate the influence of PGDHC on hallmark findings in AD.Material and MethodsCHO-7WD10 and SH-SY-5Y cells were exposed to PGDHC and lipopolysaccharide (LPS) isolated from P. gingivalis. Soluble Aβ42 peptide, amyloid precursor protein (APP), phosphorylated tau and senescence-associated secretory phenotype (SASP) factors were quantified using ELISA and Western blot assays. ResultsOur results indicate that P. gingivalis (Pg)-derived PGDHC, but not Pg-LPS, upregulated secretion of soluble Aβ42 peptide and expression of APP in CHO-7WD10 cells. Furthermore, hyperphosphorylation of tau protein was observed in SH-SY-5Y cells in response to PGDHC lipid. In contrast, Pg-LPS had little, or no significant effect on the tau phosphorylation induced in SH-SY-5Y cells. However, both PGDHC and Pg-LPS contributed to the senescence of SH-SY5Y cells as indicated by the production of senescence-associated secretory phenotype (SASP) markers, including beta-galactosidase, cathepsin B (CtsB), and pro-inflammatory cytokines TNF-α, and IL-6. Additionally, PGDHC diminished expression of the senescence-protection marker sirtuin-1 in SH-SY-5Y cells.ConclusionsAltogether, our results indicate that P. gingivalis-derived PGDHC ceramide promotes amyloidogenesis and hyperphosphorylation, as well as the production of SASP factors. Thus, PGDHC may represent a novel class of bacterial-derived virulence factors for AD associated with periodontitis.

Targeting the renin−angiotensin signaling pathway in COVID-19: Unanswered questions, opportunities, and challenges

The role of the renin−angiotensin signaling (RAS) pathway in COVID-19 has received much attention. A central mechanism for COVID-19 pathophysiology has been proposed: imbalance of angiotensin converting enzymes (ACE)1 and ACE2 (ACE2 being the severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] virus “receptor”) that results in tissue injury from angiotensin II (Ang II)-mediated signaling. This mechanism provides a rationale for multiple therapeutic approaches. In parallel, clinical data from retrospective analysis of COVID-19 cohorts has revealed that ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may be beneficial in COVID-19. These findings have led to the initiation of clinical trials using approved drugs that target the generation (ACEIs) and actions (ARBs) of Ang II. However, treatment of COVID-19 with ACEIs/ARBs poses several challenges. These include choosing appropriate inclusion and exclusion criteria, dose optimization, risk of adverse effects and drug interactions, and verification of target engagement. Other approaches related to the RAS pathway might be considered, for example, inhalational administration of ACEIs/ARBs (to deliver drugs directly to the lungs) and use of compounds with other actions (e.g., activation of ACE2, agonism of MAS1 receptors, β-arrestin−based Angiotensin receptor agonists, and administration of soluble ACE2 or ACE2 peptides). Studies with animal models could test such approaches and assess therapeutic benefit. This Perspective highlights questions whose answers could advance RAS-targeting agents as mechanism-driven ways to blunt tissue injury, morbidity, and mortality of COVID-19.

Multivalent, Soluble Nano-Self Peptides Increase Phagocytosis of Antibody-Opsonized Targets while Suppressing "Self" Signaling.

Macrophages engulf "foreign" cells and particles, but phagocytosis of healthy cells and cancer cells is inhibited by expression of the ubiquitous membrane protein CD47 which binds SIRPα on macrophages to signal "self". Motivated by some clinical efficacy of anti-CD47 against liquid tumors and based on past studies of CD47-derived polypeptides on particles that inhibited phagocytosis of the particles, here we design soluble, multivalent peptides to bind and block SIRPα. Bivalent and tetravalent nano-Self peptides prove more potent (Keff ∼ 10 nM) than monovalent 8-mers as agonists for phagocytosis of antibody opsonized cells, including cancer cells. Multivalent peptides also outcompete soluble CD47 binding to human macrophages, consistent with SIRPα binding, and the peptides suppress phosphotyrosine in macrophages, consistent with inhibition of SIRPα's "self" signaling. Peptides exhibit minimal folding, but functionality suggests an induced fit into SIRPα's binding pocket. Pre-clinical studies in mice indicate safety, with no anemia that typifies clinical infusions of anti-CD47. Multivalent nano-Self peptides thus constitute an alternative approach to promoting phagocytosis of "self", including cancer cells targeted clinically.