Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer

Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-γ induction in human PBMCs, with preservation of TLR7-driven IFN-α induction. The dendrimer was found to be superior to the imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine α-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen.This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases contract HHSN272200900033C

Design and Development of Stable, Water-soluble, Human Toll-like Receptor 2-Specific, Monoacyl Lipopeptides as Candidate Vaccine Adjuvants

Antigens in modern subunit vaccines are largely soluble and poorly immunogenic proteins inducing relatively short-lived immune responses. Appropriate adjuvants initiate early innate immune responses, amplifying subsequent adaptive immune responses. Agonists of TLR2 are devoid of significant pro-inflammatory activity in ex vivo human blood models, and yet potently adjuvantic, suggesting that this chemotype may be a safe and effective adjuvant. Our earlier work on the monoacyl lipopeptide class of TLR2 agonists led to the design of a highly potent lead, but with negligible aqueous solubility, necessitating the reintroduction of aqueous solubility. We explored several strategies of introducing ionizable groups on the lipopeptide, as well as the systematic evaluation of chemically stable bioisosteres of the ester-linked palmitoyl group. These studies have led to a fully optimized, chemically stable, and highly water-soluble, human TLR2-specific agonist, which was found to have an excellent safety profile and displayed prominent adjuvantic activities in rabbit models

Structure-Activity Relationships in Human Toll-like Receptor 2- Specific Monoacyl Lipopeptides

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. We had previously determined that at least one acyl group of optimal length (C16) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. We now show that these structurally simpler analogues display agonistic activities with human, but not murine TLR2. SAR studies on the monoacyl derivatives show that the optimal acyl chain length is C16, and aryl substituents are not tolerated. A variety of alkyl and acyl substituents on the cysteine amine were examined. All N-alkyl derivatives were inactive. In contradistinction, short-chain N-acyl analogues were found to be highly active, with a clear dependence on the chain length. A cysteine N-acetyl analogue was found to be the most potent (EC50: 1 nM), followed by the N-butyryl analogue. The N-acetyl analogue is human TLR2-specific, with its potency comparable to that of PAM2CS

Structure-Activity Relationships in Human Toll-like Receptor 8-Active 2,3-diamino-furo[2,3-c]pyridines

In our ongoing search toward identifying novel and synthetically simpler candidate vaccine adjuvants, we hypothesized that the imidazo[1,2-a]pyrazines, readily accessible via the Groebke-Blackburn-Bienaymé multicomponent reaction, would possess sufficient structural similarity with TLR7/8-agonistic imidazoquinolines. With pyridoxal as the aldehyde component, furo[2,3- c]pyridines, rather than the expected imidazo[1,2-a]pyridines were obtained, which were characterized by NMR spectroscopy and crystallography. Several analogues were found to activate TLR8-dependent NF-κB signaling. In a focused library of furo[2,3-c]pyridines, a distinct SAR was observed with varying substituents at C2. In human PBMCs, none of the furo[2,3-c]pyridines showed any proinflammatory cytokine induction, but upregulated several chemokine ligand genes. In immunization studies in rabbits, the most active compound showed prominent adjuvantic effects. The complete lack of proinflammatory cytokine induction coupled with strong adjuvantic activity of the novel furo[2,3-c]pyridines render this hitherto unknown chemotype an attractive class of compounds which are expected to be devoid of local or systemic reactogenicity

Mechanochemical synthesis of a new triptycene-based imine-linked covalent organic polymer for degradation of organic dye

In the present work, a novel triptycene-based imine-linked covalent organic polymer (TP-COP) was designed and synthesized via room-temperature, solvent-free mechanochemical grinding. The as-synthesized TP-COP material was fully characterized by Fourier transform infrared spectroscopy, solid-state NMR, field emission scanning electron microscopy (FESEM), high-resolution transmission electron microscopy (HRTEM), Brunauer-Emmett-Teller method, thermogravimetric analysis, diffuse reflectance spectroscopy (DRS), and electron paramagnetic resonance (EPR). The HRTEM image of TP-COP clearly indicates the presence of graphene-like layered morphology (exfoliated layers). The DRS study reveals that TP-COP exhibited a low optical band gap value of 2.49 eV, implying its semiconducting nature. Further, the EPR study confirmed the semiconducting behavior of TP-COP through the generation of free radicals. These findings suggest that TP-COP could be used as an efficient photocatayst for the degradation of organic dye (RhB) under solar irradiation. Moreover, TP-COP showed excellent reusability in degrading dye (RhB) without obvious performance decay

Toll-like Receptor-8 Agonistic Activities in C2, C4, and C8 Modified Thiazolo[4,5-c]quinolines

Toll-like receptor (TLR)-8 agonists typified by the 2-alkylthiazolo[4,5-c]quinolin-4-amine (CL075) chemotype are uniquely potent in activating adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds could be promising candidate vaccine adjuvants, especially for neonatal vaccines. Alkylthiazoloquinolines with methyl, ethyl, propyl and butyl groups at C2 displayed comparable TLR8-agonistic potencies; activity diminished precipitously in the C2-pentyl compound, and higher homologues were inactive. The C2-butyl compound was unique in possessing substantial TLR7-agonistic activity. Analogues with branched alkyl groups at C2 displayed poor tolerance of terminal steric bulk. Virtually all modifications at C8 led to abrogation of agonistic activity. Alkylation on the C4-amine was not tolerated, whereas N-acyl analogues with short acyl groups (other than acetyl) retained TLR8 agonistic activity, but were substantially less water-soluble. Immunization in rabbits with a model subunit antigen adjuvanted with the lead C2-butyl thiazoloquinoline showed enhancements of antigen-specific antibody titers

Mechanochemical synthesis of a new triptycene-based imine-linked covalent organic polymer for degradation of organic dye

In the present work, a novel triptycene-based imine-linked covalent organic polymer (TP-COP) was designed and synthesized via room-temperature, solvent-free mechanochemical grinding. The as-synthesized TP-COP material was fully characterized by Fourier transform infrared spectroscopy, solid-state NMR, field emission scanning electron microscopy (FESEM), high-resolution transmission electron microscopy (HRTEM), Brunauer-Emmett-Teller method, thermogravimetric analysis, diffuse reflectance spectroscopy (DRS), and electron paramagnetic resonance (EPR). The HRTEM image of TP-COP clearly indicates the presence of graphene-like layered morphology (exfoliated layers). The DRS study reveals that TP-COP exhibited a low optical band gap value of 2.49 eV, implying its semiconducting nature. Further, the EPR study confirmed the semiconducting behavior of TP-COP through the generation of free radicals. These findings suggest that TP-COP could be used as an efficient photocatayst for the degradation of organic dye (RhB) under solar irradiation. Moreover, TP-COP showed excellent reusability in degrading dye (RhB) without obvious performance decay

Emerging Standards and the Hybrid Model for Organizing Scientific Events During and After The COVID-19 Pandemic

Artigo publicado em revista científica internacionalSince the beginning of 2020, the COVID-19 pandemic has dramatically influenced almost every aspect of human life. Activities requiring human gatherings have either been postponed, cancelled, or held completely virtually. To supplement lack of in-person contact, people have increasingly turned to virtual settings on-line, advantages of which include increased inclusivity and accessibility and reduction of carbon footprint. However, emerging online technologies cannot fully replace, in-person scientific events. In-person meetings are not susceptible to poor internet connectivity problems, and they provide novel opportunities for socialization, creating new collaborations, and sharing ideas. To continue such activities, a hybrid model for scientific events could be a solution offering both in-person and virtual components. While participants can freely choose the mode of their participation, virtual meetings would most benefit those who cannot attend in-person due to the limitations. In-person portions of meetings should be organized with full consideration of prevention and safety strategies including risk assessment and mitigation, venue and environmental sanitation, participant protection and disease prevention, and promoting the hybrid model. This new way of interaction between scholars can be considered as a part of a resilience system which was neglected previously and should become a part of routine practice in scientific community.info:eu-repo/semantics/publishedVersio

Recent advances in steroid amino acid conjugates: Old scaffolds with new dimensions

Hybrid chemical compounds formed by conjugation of two or more bioactive molecules have shown wide variety of applications in biology, microelectronics as well as material sciences. In particular, the conjugates of steroid framework are known to have broad biological activity profile due to their ability to penetrate the biomembranes and bind to specific hormone receptors. Among the various conjugates of steroids, Steroid Amino Acid Conjugates (SAACs) are attractive because of the possibility of fine tuning of the amphiphilicity with position, orientation and nature of amino acids. The structural details, applications, mechanistic insights and their diverse pharmacological as well as other physicochemical properties of several SAACs are summarized in the present review. This review provides better insight for medicinal chemists to design and explore such novel conjugates which can be used as lead structures in the future drug discovery or as probes to understand the complex biological system