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Journal ArticleDOI

Synthetic Toll-like receptor agonists for the development of powerful malaria vaccines: a patent review

TL;DR: TLR agonists are promising adjuvants for the development of effective malaria vaccine, allowing for both innate inflammatory responses as well as the induction of adaptive immunity.
Abstract: Introduction: Currently, there is no efficient vaccine available against clinical malaria. However, continuous efforts have been committed to develop powerful antimalarial vaccine by discovery of n...
Citations
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01 Jul 2013
TL;DR: Use of this platform to deliver a model whole‐protein vaccine with optimized release kinetics resulted in >10‐fold increases in antigen‐specific T‐cell and humoral immune responses relative to traditional parenteral needle‐based immunization.
Abstract: Microneedle vaccines mimic several aspects of cutaneous pathogen invasion by targeting antigen to skin-resident dendritic cells and triggering local infl ammatory responses in the skin, which are correlated with enhanced immune responses. Here, we tested whether control over vaccine delivery kinetics can enhance immunity through further mimicry of kinetic profi les present during natural acute infections. An approach for the fabrication of silk/poly(acrylic acid) (PAA) composite microneedles composed of a silk tip supported on a PAA base is reported. On brief application of microneedle patches to skin, the PAA bases rapidly dissolved to deliver a protein subunit vaccine bolus, while also implanting persistent silk hydrogel depots into the skin for a low-level sustained cutaneous vaccine release over 1‐2 weeks. Use of this platform to deliver a model whole-protein vaccine with optimized release kinetics resulted in > 10-fold increases in antigen-specifi c T-cell and humoral immune responses relative to traditional parenteral needle-based immunization. compared with traditional parenteral immunization approaches targeting less immunogenic tissues such as muscle (reviewed elsewhere). [ 1 ] Microneedle vaccination has in many cases also outperformed hypodermic needle-based delivery to the skin, suggesting the importance of factors relating to microneedle delivery itself, such as the infl ammatory state generated by micrometer-scale wounding following microneedle insertion. [ 2 , 3 ] Unrelated studies have begun to reveal the importance of antigen and adjuvant delivery kinetics in the developing immune response, both within the context of vaccination and in natural responses to infection. [ 4‐7 ] For example, the magnitude, functionality, and phenotype of CD8 + T-cell responses can be shaped by immunizations where antigen or adjuvant delivery kinetics are controlled over multi-week periods, with persistent antigenic and infl ammatory signals eliciting stronger responses than transient bolus vaccine exposure. [ 4 , 5 ] These fi ndings are consistent with known differences in the natural immunity generated against transient versus persistent pathogens, indicating specifi c mechanisms of immunity that may be exploited through engineered kinetics to yield greater vaccine effi cacy. We have recently begun to explore the combination of these two approaches for enhancing immunogenicity, through the

107 citations

01 Nov 2010
TL;DR: A new bifunctional layer-by-layer (LbL) construct made by combining a permanent microbicidal polyelectrolyte multilayered (PEM) base film with a hydrolytically degradable PEM top film that offers controlled and localized delivery of therapeutics is presented.
Abstract: Here we present a new bifunctional layer-by-layer (LbL) construct made by combining a permanent microbicidal polyelectrolyte multilayered (PEM) base film with a hydrolytically degradable PEM top film that offers controlled and localized delivery of therapeutics. Two degradable film architectures are presented: (1) bolus release of an antibiotic (gentamicin) to eradicate initial infection at the implant site, or (2) sustained delivery of an anti-inflammatory drug (diclofenac) to cope with inflammation at the site of implantation due to tissue injury. Each degradable film was built on top of a permanent base film that imparts the implantable device surface with microbicidal functionality that prevents the formation of biofilms. Controlled-delivery of gentamicin was demonstrated over hours and that of diclofenac over days. Both drugs retained their efficacy upon release. The permanent microbicidal base film was biocompatible with A549 epithelial cancer cells and MC3T3-E1 osteoprogenitor cells, while also pre...

105 citations

Journal ArticleDOI
TL;DR: This perspective will highlight the recent discoveries in this field emphasizing the role of TLR isoforms in different diseases, the therapeutic effect of their natural and synthetic modulators and will discuss insights for the future exploitation of TLRs modulators in human health.
Abstract: Toll-like receptors (TLRs) are a class of proteins that recognize pathogen-associated molecular patterns (PAMPs) and damaged-associated molecular patterns (DAMPs), and they are involved in the regulation of innate immune system. These transmembrane receptors, localized at the cellular or endosomal membrane, trigger inflammatory processes through either myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling pathways. In the last decades, extensive research has been performed on TLR modulators and their therapeutic implication under several pathological conditions, spanning from infections to cancer, from metabolic disorders to neurodegeneration and autoimmune diseases. This Perspective will highlight the recent discoveries in this field, emphasizing the role of TLRs in different diseases and the therapeutic effect of their natural and synthetic modulators, and it will discuss insights for the future exploitation of TLR modulators in human health.

54 citations

Journal ArticleDOI
TL;DR: A detailed SAR in TLR2 agonistic scaffolds and also covered the design and chemistry for the conjugation of TLR 2 agonists to antigens, carbohydrates, polymers, and fluorophores are elaborated in this paper.
Abstract: Toll-like receptors (TLRs) are the pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) in microbial species. Among the various TLRs, TLR2 has a special place due to its ability to sense the widest repertoire of PAMPs owing to its heterodimerization with either TLR1 or TLR6, broadening its ligand diversity against pathogens. Various scaffolds are reported to activate TLR2, which include naturally occurring lipoproteins, synthetic lipopeptides, and small heterocyclic molecules. We described a detailed SAR in TLR2 agonistic scaffolds and also covered the design and chemistry for the conjugation of TLR2 agonists to antigens, carbohydrates, polymers, and fluorophores. The approaches involved in delivery of TLR2 agonists such as lipidation of antigen, conjugation to polymers, phosphonic acids, and other linkers to achieve surface adsorption, liposomal formulation, and encapsulating nanoparticles are elaborated. The crystal structure analysis and computational modeling are also included with the structural features that facilitate TLR2 activation.

14 citations

Journal ArticleDOI
21 Jul 2021
TL;DR: TLR7/8 agonists are emerging as promising vaccine adjuvant candidates and the present SAR and structural information will provide a road map towards the identification of more potent and appropriate candidates for further drug discovery.
Abstract: Several synthetic heterocyclic small molecules like imiquimod, resiquimod, CL097, CL075, bromopirone, tilorone, loxoribine and isatoribine demonstrated TLR7/8 agonistic activity and relatively modest structural changes in such molecules result in major variation in the TLR7 and/or TLR8 activity. A strict dependency of the electronic configuration of the heterocyclic system was also observed to influence the agonistic activity. In the present review, an evolution of imidazole based TLR7/8 agonist from imidazoquinoline based scaffold is delineated along with the elaboration of detailed structure activity relationship (SAR) in each chemotype. The structural and activity details of not only the active compounds but also the related inactive compounds are included to better understand the SAR. TLR7/8 agonists are emerging as promising vaccine adjuvant candidates and the present SAR and structural information will provide a road map towards the identification of more potent and appropriate candidates for further drug discovery.

8 citations

References
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Journal ArticleDOI
TL;DR: Rapid progress that has recently improved the understanding of the molecular mechanisms that mediate TLR signalling is reviewed.
Abstract: One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through the Toll-like receptors (TLRs), which recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also instructs the development of antigen-specific acquired immunity. Here, we review the rapid progress that has recently improved our understanding of the molecular mechanisms that mediate TLR signalling.

7,906 citations

Journal ArticleDOI
19 Mar 2010-Cell
TL;DR: The role of PRRs, their signaling pathways, and how they control inflammatory responses are discussed.

6,987 citations

Journal ArticleDOI
27 May 2011-Immunity
TL;DR: The role played by TLRs in mounting protective immune responses against infection and their crosstalk with other PRRs with respect to pathogen recognition is focused on.

3,113 citations

Journal ArticleDOI
TL;DR: Possible areas of application for polyelectrolyte shells range from the pharmaceutical, food, cosmetic, and paint industries to catalysis and microcrystallization.
Abstract: Exact control of the film thickness of polyelectrolyte shells (a transmission electron microscopy image is shown) is achieved by colloid-templated consecutive adsorption of polyanions and polycations followed by decomposition of the templating core. Possible areas of application for these shells range from the pharmaceutical, food, cosmetic, and paint industries to catalysis and microcrystallization.

1,768 citations

Journal ArticleDOI
TL;DR: The potential benefits and importance of formulation and mechanisms of action of adjuvants are outlined and safety considerations are emphasized in the clinical development of effective adjuvant that will help facilitate effective next-generation vaccines against devastating infectious diseases.
Abstract: Vaccines containing novel adjuvant formulations are increasingly reaching advanced development and licensing stages, providing new tools to fill previously unmet clinical needs. However, many adjuvants fail during product development owing to factors such as manufacturability, stability, lack of effectiveness, unacceptable levels of tolerability or safety concerns. This Review outlines the potential benefits of adjuvants in current and future vaccines and describes the importance of formulation and mechanisms of action of adjuvants. Moreover, we emphasize safety considerations and other crucial aspects in the clinical development of effective adjuvants that will help facilitate effective next-generation vaccines against devastating infectious diseases.

983 citations