Reproducing the Reaction Route Map on the Shape Space from Its Quotient by the Complete Nuclear Permutation-Inversion Group.

This study develops an algorithm to reproduce reaction route maps (RRMs) in the shape space from the outputs of potential search algorithms. To demonstrate the algorithm, global reaction route mapping is utilized as a potential search algorithm, but the proposed algorithm should work with other potential search algorithms in principle. The proposed algorithm does not require any encoding of the molecular configurations and is thus applicable to complicated realistic molecules for which efficient encoding is not readily available. We show that subgraphs of an RRM mapped to each other by the action of the symmetry group are isomorphic and also provide an algorithm to compute the set of feasible transformations in the sense of Longuet-Higgins. We demonstrate the proposed algorithm in toy models and in more realistic molecules. Finally, we remark on absolute rate theory from our perspective.

Characterizing Reaction Route Map of Realistic Molecular Reactions Based on Weight Rank Clique Filtration of Persistent Homology.

A reaction route map (RRM) constructed using the GRRM program is a collection of elementary reaction pathways, each of which comprises two equilibrium (EQ) geometries and one transition state (TS) geometry connected by an intrinsic reaction coordinate (IRC). An RRM can be mathematically represented by a graph with weights assigned to both vertices, corresponding to EQs, and edges, corresponding to TSs, representing the corresponding energies. In this study, we propose a method to extract topological descriptors of a weighted graph representing an RRM based on persistent homology (PH). The work of Mirth et al. [ J. Chem. Phys. 2021, 154, 114114], in which PH analysis was applied to the (3N - 6)-dimensional potential energy surface of an N atomic system, is related to the present method, but our method is practically applicable to realistic molecular reactions. Numerical assessments revealed that our method can extract the same information as the method proposed by Mirth et al. for the 0-th and 1-st PHs, except for the death of the 1-st PH. In addition, the information obtained from the 0-th PH corresponds to the analysis using the disconnectivity graph. The results of this study suggest that the descriptors obtained using the proposed method accurately reflect the characteristics of the chemical reactions and/or physicochemical properties of the system.

Post-fusion influenza vaccine adjuvanted with SA-2 confers heterologous protection via Th1-polarized, non-neutralizing antibody responses.

Development of a universal influenza vaccine that can provide robust and long-lasting protection against heterologous infections is a global public health priority. A variety of vaccine antigens are designed to increase the antigenicity of conserved epitopes to elicit cross-protective antibodies that often lack virus-neutralizing activity. Given the contribution of antibody effector functions to cross-protection, adjuvants need to be added to modulate antibody effector functions as well as to enhance antibody quantity. We previously showed that post-fusion influenza vaccine antigens elicit non-neutralizing but cross-protective antibodies against conserved epitopes. Here, using a murine model, we comparably assessed the adjuvanticity of the newly developed SA-2 adjuvant containing a synthetic TLR7 agonist DSP-0546 and squalene-based MF59 analog as representative Th1- or Th2-type adjuvants, respectively. Both types of adjuvants in the post-fusion vaccine comparably enhanced cross-reactive IgG titers against heterologous strains. However, only SA-2 skewed the IgG subclass into the IgG2c subclass in association to its Th1-polarizing nature. SA-2-enhanced IgG2c responses exhibited antibody-dependent cellular cytotoxicity against heterologous virus strains, without cross-neutralizing activity. Eventually, the SA-2-adjuvanted vaccination provided protection against lethal infection by heterologous H3N2 and H1N1 viruses. Together, we conclude that the combination with a SA-2 is advantageous for enhancing the cross-protective capability of post-fusion HA vaccines that elicit non-neutralizing IgG antibodies.

Antibodies against a short region of PfRipr inhibit Plasmodium falciparum merozoite invasion and PfRipr interaction with Rh5 and SEMA7A.

Plasmodium falciparum merozoite invasion into erythrocytes is an essential step of the blood-stage cycle, survival of parasites, and malaria pathogenesis. P. falciparum merozoite Rh5 interacting protein (PfRipr) forms a complex with Rh5 and CyRPA in sequential molecular events leading to erythrocyte invasion. Recently we described PfRipr as a conserved protein that induces strain-transcending growth inhibitory antibodies in in vitro assays. However, being a large and complex protein of 1086 amino acids (aa) with 87 cysteine residues, PfRipr is difficult to express in conventional expression systems towards vaccine development. In this study we sought to identify the most potent region of PfRipr that could be developed to overcome difficulties related to protein expression, as well as to elucidate the invasion inhibitory mechanism of anti-PfRipr antibodies. Using the wheat germ cell-free system, Ecto- PfRipr and truncates of approximately 200 aa were expressed as soluble proteins. We demonstrate that antibodies against PfRipr truncate 5 (PfRipr_5: C720-D934), a region within the PfRipr C-terminal EGF-like domains, potently inhibit merozoite invasion. Furthermore, the antibodies strongly block PfRipr/Rh5 interaction, as well as that between PfRipr and its erythrocyte-surface receptor, SEMA7A. Taken together, PfRipr_5 is a potential candidate for further development as a blood-stage malaria vaccine.

Dihydropyrrolo[2,3-d]pyrimidines: Selective Toll-Like Receptor 9 Antagonists from Scaffold Morphing Efforts.

Toll-like receptors (TLRs) play important roles in the innate immune system. In fact, recognition of endogenous immune complexes containing self-nucleic acids as pathogen- or damage-associated molecular patterns contributes to certain autoimmune diseases, and inhibition of these recognition signals is expected to have therapeutic value. We identified dihydropyrrolo[2,3-d]pyrimidines as novel selective TLR9 antagonists with high aqueous solubility. A structure-activity relationship study of a known TLR9 antagonist led to the promising compound 18, which showed potent TLR9 antagonistic activity, sufficient aqueous solubility for parenteral formulation, and druggable properties. Compound 18 suppressed the production of the proinflammatory cytokine IL-6 in CpG-induced mouse model. It is therefore believed that compound 18 has great potential in the treatment of TLR9-mediated systemic uncontrollable inflammatory response like sepsis.

Synthesis and evaluation of 6-nitro-7-(1-piperazino)quinazolines: dual-acting compounds with inhibitory activities toward both tumor necrosis factor-alpha (TNF-alpha) production and T cell proliferation.

We investigated the chemical modifications of the nitroquinazoline derivative (1) through the replacement of the NH group at the C(4)-position with several N-alkyl groups to increase the lipophilicity at the C(4)-position. Among them, we found that the N-methyl analogue (5a) showed a 2-fold loss in the inhibitory activity toward tumor necrosis factor-alpha (TNF-alpha) production in vitro as compared with the NH analogue (1); however, 5a exhibited an oral inhibitory activity on TNF-alpha production with an ED50 value of 26 mg/kg, whereas 1 did not. Moreover, the oral bioavailability of 5a was higher than that of 1 (1, F=1%; 5a, F=21%), and the calculated ClogP value for 5a was higher than that for 1. These results suggest that the improved lipophilicity of 5a compared with that of 1 reflects its greater inhibitory activity on TNF-alpha production in vivo as well as oral bioavailability.