Accelerating drug target inhibitor discovery with a deep generative foundation model

Inhibitor discovery for emerging drug-target proteins is challenging, especially when target structure or active molecules are unknown. Here, we experimentally validate the broad utility of a deep generative framework trained at-scale on protein sequences, small molecules, and their mutual interactions-unbiased toward any specific target. We performed a protein sequence-conditioned sampling on the generative foundation model to design small-molecule inhibitors for two dissimilar targets: the spike protein receptor-binding domain (RBD) and the main protease from SARS-CoV-2. Despite using only the target sequence information during the model inference, micromolar-level inhibition was observed in vitro for two candidates out of four synthesized for each target. The most potent spike RBD inhibitor exhibited activity against several variants in live virus neutralization assays. These results establish that a single, broadly deployable generative foundation model for accelerated inhibitor discovery is effective and efficient, even in the absence of target structure or binder information

IL-1β Promotes TGF-β1 and IL-2 Dependent Foxp3 Expression in Regulatory T Cells

Earlier, we have shown that GM-CSF-exposed CD8α− DCs that express low levels of pro-inflammatory cytokines IL-12 and IL-1β can induce Foxp3+ Tregs leading to suppression of autoimmunity. Here, we examined the differential effects of IL-12 and IL-1β on Foxp3 expression in T cells when activated in the presence and absence of DCs. Exogenous IL-12 abolished, but IL-1β enhanced, the ability of GM-CSF-exposed tolerogenic DCs to promote Foxp3 expression. Pre-exposure of DCs to IL-1β and IL-12 had only a modest effect on Foxp3− expressing T cells; however, T cells activated in the absence of DCs but in the presence of IL-1β or IL-12 showed highly significant increase and decrease in Foxp3+ T cell frequencies respectively suggesting direct effects of these cytokines on T cells and a role for IL-1β in promoting Foxp3 expression. Importantly, purified CD4+CD25+ cells showed a significantly higher ability to maintain Foxp3 expression when activated in the presence of IL-1β. Further analyses showed that the ability of IL-1β to maintain Foxp3 expression in CD25+ T cells was dependent on TGF-β1 and IL-2 expression in Foxp3+Tregs and CD25− effectors T cells respectively. Exposure of CD4+CD25+ T cells to IL-1β enhanced their ability to suppress effector T cell response in vitro and ongoing experimental autoimmune thyroidits in vivo. These results show that IL-1β can help enhance/maintain Tregs, which may play an important role in maintaining peripheral tolerance during inflammation to prevent and/or suppress autoimmunity

Enhanced sensitivity and selectivity in lithium ion recognition property of an oligomeric squaraine dye based fluorescent sensor

A novel fluorescent sensor based on a pyrrole-derived &#960; -conjugated oligosquaraine containing diethylene glycol monomethyl ether side chain has been synthesized. This molecular wire based fluorescent sensor showed enhanced sensitiviy and specificity towards the recognition of Li<SUP>+</SUP> when compared to Na<SUP>+</SUP> and K<SUP>+</SUP>. An analogous simple squaraine dye could not sense any of the metal ions

Synthesis and properties of water-soluble squaraine oligomers containing pendant propanesulfonate moieties

Polycondensation of squaric acid with a water-soluble pyrrole derivative containing an N-propanesulfonate pendant group gave a water-soluble A-B type oligomer. Similarly, several water-soluble random oligomers were prepared by the polycondensation of pyrrole, sodium 3-(pyrrol-1-yl)propanesulfonate, and squaric acid. Molecular weight analysis of the new oligomers showed a low degree of polymerization (Mn ~ 1800-2000) due to the premature precipitation of the condensation products in the reaction medium. Comparison of the IR and 1H NMR spectral data of the new oligomers with those of a model squaraine dye, 9, revealed the presence of zwitterionic squaraine repeat units. The negative solvatochromic property of the polycondensation products and the model compound 9 was analogous to that of several reported squaraine dyes, indicating their structural similarities. Comparison of the solvatochromic properties of the polycondensation products with that of the model dye 9 revealed the oligomeric nature of the polycondensation products. All new oligomers showed enhanced conductivities without external doping when compared to an analogous material without pendant propanesulfonate groups. For example, the conductivity of the condensation product of squaric acid with pyrrole was 1.1 &#215; 10-6 S/cm, whereas that of the condensation product of squaric acid and sodium 3-(pyrrol-1-yl)propanesulfonate was 3.2 &#215; 10-5 S/cm. The enhanced conductivities of the new squaraine oligomers could be due to enhanced conjugation or due to intramolecular doping by the pendant propanesulfonate groups

Synthesis and properties of alternating acceptor-donor copolymers of squaric acid with 1-dodecyl- and 3-dodecylpyrroles

Polycondensation between the acceptor-donor monomer combination of squaric acid with 1-dodecyl- and 3-dodecylpyrroles provided conjugated macromolecules having two types of isomeric repeating units, depending upon the reaction conditions employed. Under azeotropic distillation using the 1-butanol-benzene solvent mixture (route A), the most preferred 1,3-zwitterionic repeating units were mostly formed, whereas in DMSO-acetic acid solvent under room temperature (route B), considerable amounts of the isomeric 1,2-diketonic repeating units were also formed along with the zwitterionic repeating units. Evidence for the structural differences of the polycondensation products obtained by routes A and B could be obtained from the detailed IR spectral analysis and studies of their physical properties such as solubility, molecular weight, optical absorption, solvatochromism, and conducting properties. The solubilities and the molecular weights of the polycondensation products having 1,2-diketonic repeating units obtained by route B were significantly enhanced when compared to those obtained as per route A. The UV-vis spectral and solvatochromic properties of the polymers obtained by routes A and B showed distinct differences, which were in accordance with their proposed structures. The electrical conductivities of the polymers obtained from 3-dodecylpyrrole and squaric acid by route B showed better values over polymers obtained through route A

Squaraine dye based molecular wires containing flexible oxyethylene chains as sensors. Enhanced fluorescence response on Li<SUP>+</SUP> recognition

Two new pyrrole-derived squaraine molecular wires 4a and 4b containing flexible oxyethylene side chains have been prepared and characterized. GPC analysis of 4a and 4b showed molecular weights of nearly 1800 g/mol. The UV-vis absorption maxima of these molecular wires were broad and red-shifted (11-12 nm) when compared to that of a model squaraine dye 7a. Nevertheless, the absorption maxima of the molecular wires 4a and 4b were much lower than the expected values despite their extended conjugation which could be due to the reduced charge-transfer interactions in these systems. Addition of alkali metal ions such as Li+, Na+, and K+ could not produce considerable changes in the absorption properties of the molecular wires except a marginal change in the case of 4a on addition of Li+. However, significant changes in the emission characteristics could be noticed in the case of 4a upon addition of Li+, whereas addition of K+ and Na+ did not produce any measurable response. Interestingly, the absorption and emission characteristics of the monomeric squaraine dyes 7a and 7b showed only marginal response upon the addition of Li+, Na+, and K+. The enhanced response of the molecular wire 4a over the monomeric squaraine dye 7a has been explained on the basis of the optimum chain length of the flexible binding site and due to a collective system response of the molecular wire, which is associated with a flexible to a rigid conformational change upon the alkali metal ion binding