Breadth Of Reactivity Research Articles

Synthesis, characterisation, and catalytic application of a soluble molecular carrier of sodium hydride activated by a substituted 4-(dimethylamino)pyridine

Recently main group compounds have stepped into the territory of precious transition metal compounds with respect to utility in the homogeneous catalysis of fundamentally important organic transformations. Inspired by the need to promote more sustainability in chemistry because of their greater abundance in nature, this change of direction is surprising since main group metals generally do not possess the same breadth of reactivity as precious transition metals. Here, we introduce the dihydropyridylsodium compound, Na-1,2-tBu-DH(DMAP), and its monomeric variant [Na-1,2-tBu-DH(DMAP)]·Me6TREN, and demonstrate their effectiveness in transfer hydrogenation catalysis of the representative alkene 1,1-diphenylethylene to the alkane 1,1-diphenylethane using 1,4-cyclohexadiene as hydrogen source [DMAP = 4-dimethylaminopyridine; Me6TREN = tris(N,N-dimethyl-2-aminoethyl)amine]. Sodium is appealing because of its high abundance in the earth’s crust and oceans, but organosodium compounds have been rarely used in homogeneous catalysis. The success of the dihydropyridylsodium compounds can be attributed to their high solubility and reactivity in organic solvents.

Vitamin B12 in Photocatalysis - An Underexplored Frontier in Cooperative Catalysis.

Vitamin B12 (VB12) is a flexible and sustainable catalyst both in nature and the reaction flask, facilitating varied organic transformations of high value to both enzymatic processes and synthetic chemists. Key to this value is the breadth of reactivity it possesses, capable of both ionic, 2 electron chemistry, and radical, 1 electron chemistry. In particular, the ability to generate carbon-centered radical intermediates via photolysis of organocobalt intermediates formed from alkyl electrophiles opens the door to powerful new radical transformations challenging to achieve using classical photoredox or ligand-to-metal charge transfer (LMCT) catalysis. While this unique photocatalytic reactivity of VB12 has been increasingly leveraged in monocatalytic schemes, recent reports have demonstrated VB12 is able to function as the photocatalytic component in cooperative schemes, driving diverse reactivity including remote elimination of alkyl halides, regioselective epoxide arylation, and regioselective epoxide reduction. This concept briefly overviews the enabling photochemical properties of VB12 and recent applications in cooperative catalysis, providing a framework for the continued development of new cooperative catalyst systems using this powerful photoactive complex.

Long Term Immune Response Produced by the SputnikV Vaccine.

SputnikV is a vaccine against SARS-CoV-2 developed by the Gamaleya National Research Centre for Epidemiology and Microbiology. The vaccine has been shown to induce both humoral and cellular immune responses, yet the mechanisms remain largely unknown. Forty SputnikV vaccinated individuals were included in this study which aimed to demonstrate the location of immunogenic domains of the SARS-CoV-2 S protein using an overlapping peptide library. Additionally, cytokines in the serum of vaccinated and convalescent COVID-19 patients were analyzed. We have found antibodies from both vaccinated and convalescent sera bind to immunogenic regions located in multiple domains of SARS-CoV-2 S protein, including Receptor Binding Domain (RBD), N-terminal Domain (NTD), Fusion Protein (FP) and Heptad Repeats (HRs). Interestingly, many peptides were recognized by immunized and convalescent serum antibodies and correspond to conserved regions in circulating variants of SARS-CoV-2. This breadth of reactivity was still evident 90 days after the first dose of the vaccine, showing that the vaccine has induced a prolonged response. As evidenced by the activation of T cells, cellular immunity strongly suggests the high potency of the SputnikV vaccine against SARS-CoV-2 infection.

IgV somatic mutation of human anti-SARS-CoV-2 monoclonal antibodies governs neutralization and breadth of reactivity.

Abs that neutralize SARS-CoV-2 are thought to provide the most immediate and effective treatment for those severely afflicted by this virus. Because coronavirus potentially diversifies by mutation, broadly neutralizing Abs are especially sought. Here, we report a possibly novel approach to rapid generation of potent broadly neutralizing human anti–SARS-CoV-2 Abs. We isolated SARS-CoV-2 spike protein–specific memory B cells by panning from the blood of convalescent subjects after infection with SARS-CoV-2 and sequenced and expressed Ig genes from individual B cells as human mAbs. All of 43 human mAbs generated in this way neutralized SARS-CoV-2. Eighteen of the forty-three human mAbs exhibited half-maximal inhibitory concentrations (IC50) of 6.7 × 10–12 M to 6.7 × 10–15 M for spike-pseudotyped virus. Seven of the human mAbs also neutralized (with IC50 < 6.7 × 10–12 M) viruses pseudotyped with mutant spike proteins (including receptor-binding domain mutants and the S1 C-terminal D614G mutant). Neutralization of the Wuhan Hu-1 founder strain and of some variants decreased when coding sequences were reverted to germline, suggesting that potency of neutralization was acquired by somatic hypermutation and selection of B cells. These results indicate that infection with SARS-CoV-2 evokes high-affinity B cell responses, some products of which are broadly neutralizing and others highly strain specific. We also identify variants that would potentially resist immunity evoked by infection with the Wuhan Hu-1 founder strain or by vaccines developed with products of that strain, suggesting evolutionary courses that SARS-CoV-2 could take.

Mechanism of Binding to Ebola Virus Glycoprotein by the ZMapp, ZMAb, and MB-003 Cocktail Antibodies.

Cocktails of monoclonal antibodies (MAbs) that target the surface glycoprotein (GP) of Ebola virus (EBOV) are effective in nonhuman primate models and have been used under emergency compassionate-treatment protocols in human patients. However, the amino acids that form the detailed binding epitopes for the MAbs in the ZMapp, ZMAb, and the related MB-003 cocktails have yet to be identified. Other binding properties that define how each MAb functionally interacts with GP—such as affinity, epitope conservation, and epitope accessibility—also remain largely unknown. To help define how each MAb interacts with GP, here we used comprehensive alanine-scanning mutagenesis (shotgun mutagenesis), neutralization escape, and whole virion binding to define each MAb's specific epitope, epitope accessibility, epitope conservation, and apparent affinity. Each of the six therapeutic MAbs binds nonidentical epitopes in the GP base, glycan cap, or mucin-like domain. Their apparent affinity, epitope complementarity, and epitope accessibility helps explain why MAbs 4G7 and 13C6 are more protective than 2G4 and 1H3. The mucin-like domain MAbs 6D8 and 13F6 bind with the strongest apparent affinity, helping to explain their effectiveness in vivo despite their inability to neutralize virus. Ebola virus disease (EVD) can be caused by four different filovirus family members, including Ebola virus (EBOV), which infected 10 times more people in western Africa over the last year than all previous EVD outbreaks combined, with a number of cases distributed across the globe by travelers. Cocktails of inhibitory monoclonal antibodies (MAbs), such as ZMAb, MB-003, and in particular ZMapp, have demonstrated in animal models some of the most significant therapeutic potential for treating EVD, and in 2014, 15 patients were treated with ZMapp or ZMAb under compassionate-use protocols. Here, we have defined the epitope features for the most important therapeutic MAbs against EBOV developed to date. Defining the epitopes and binding characteristics for these MAbs, as well as the commonly used reference MAb KZ52, helps explain their breadth of reactivity against different ebolavirus species, predict viral evasion against these MAbs, and design new cocktails of MAbs with improved complementarity.

Computational Prediction of Neutralization Epitopes Targeted by Human Anti-V3 HIV Monoclonal Antibodies

The extreme diversity of HIV-1 strains presents a formidable challenge for HIV-1 vaccine design. Although antibodies (Abs) can neutralize HIV-1 and potentially protect against infection, antibodies that target the immunogenic viral surface protein gp120 have widely variable and poorly predictable cross-strain reactivity. Here, we developed a novel computational approach, the Method of Dynamic Epitopes, for identification of neutralization epitopes targeted by anti-HIV-1 monoclonal antibodies (mAbs). Our data demonstrate that this approach, based purely on calculated energetics and 3D structural information, accurately predicts the presence of neutralization epitopes targeted by V3-specific mAbs 2219 and 447-52D in any HIV-1 strain. The method was used to calculate the range of conservation of these specific epitopes across all circulating HIV-1 viruses. Accurately identifying an Ab-targeted neutralization epitope in a virus by computational means enables easy prediction of the breadth of reactivity of specific mAbs across the diversity of thousands of different circulating HIV-1 variants and facilitates rational design and selection of immunogens mimicking specific mAb-targeted epitopes in a multivalent HIV-1 vaccine. The defined epitopes can also be used for the purpose of epitope-specific analyses of breakthrough sequences recorded in vaccine clinical trials. Thus, our study is a prototype for a valuable tool for rational HIV-1 vaccine design.

A multiclade DNA/Ad vaccines for AIDS: the present and next generation

Development of an effective vaccine against HIV has proven to be particularly challenging to the scientific community in the absence of naturally occurring, protective immune responses. Current vaccine candidates target multiple internal and external gene product. Next generation vaccines will need to enhance the immunogenicity of the envelope (Env), with the goal of improving the breadth of the neutralizing antibody response while concurrently stimulating cell-mediated immunity. However, the envelope's genetic diversity and multiple mechanisms for evading the human immune system have made it difficult to design successful candidates. Efforts at the Vaccine Research Center have centered on the use of genetic and structural biological information to improve Env immunogen design. The genetic approach has focused on the conserved regions and conserved subdomains of variable regions. To target such conserved domains, site-specific mutagenesis has been employed to generate and analyze variant and chimeric Env proteins. Immunization studies suggest that the V3 region plays a dominant role in eliciting neutralization of viruses from different clades, and some breadth of reactivity among V3 regions is observed. The status of the structure-based immunogen design effort and the status of the current human multiclade and multigene vaccine candidate will be reviewed.

Induction of immune responses against human papillomaviruses by hypervariable epitope constructs.

An ideal prophylactic vaccine against human papillomaviruses (HPV) would be one that can induce broadly reactive antibody titres to at least the major oncogenic strains of HPV. It has been previously shown that HPV structural proteins are highly immunogenic but fail to elicit cross-reactive immune responses against heterologous strains of HPV. Recent studies have demonstrated that the immunity induced by virus-like particles is mostly type specific. In the present study, we determined the breadth of reactivity of antibodies induced in mice immunized with hypervariable epitope constructs (HECs), which represent sequence variants of immunodominant B-cell epitopes of the major capsid protein L1 of HPV. In order to test the breadth of reactivity, sera from immunized mice were tested against peptides representing analogous sequences of HPV types 16, 18, 31 and 45. Mice immunized with HECs based on two epitopes mounted antibody responses that cross-reacted with two different analogues, 16 and 18. Significantly, antibodies from mice immunized with HECs also inhibited haemagglutination mediated by HPV-16 L1 VLPs, suggesting that immunization resulted in the development of antibodies that could bind to viral capsid proteins in their native conformation. Our observations suggest that HECs may overcome the restriction of type specific immunity against HPV.

Preservation of fossil biopolymeric structures: Conclusive immunological evidence

Immunological assays are highly favoured for their ability to readily discriminate subtle structural differences in complex biopolymers, such as proteins and polysaccharides. Immunological reactions previously reported with extracts from biominerals at least 70 Myr old have fuelled hopes that such biopolymeric structures can survive the process of fossilization. We have raised antibodies against biopolymers from a range of Recent brachiopod shells to reconstruct a fine-grained pattern of phylogenetic relationships. Using the same antibodies, the phylogenetic affinities of fossil relatives were tested. Immunological reaction patterns for Plio-Pleistocene shells were essentially identical to the patterns of modern shells (although the breadth of reactivity was narrowed) and entirely consistent with current systematic interpretations. Older samples (>4–21 Myr) were immunologically reactive, but failed to satisfy the criterion of systematic specificity. Our results provide an unequivocal demonstration that original macromolecular structures capable of yielding systematic information are preserved and accessible for immunological analysis for at least two million years. Non-specific reactions observed with the older material may relate in part to formation of mineral-induced diagenetic determinants (MIDDs).