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Biology subjects

Shaul, J.

Publications and source records attributed to Shaul, J..

4 recordsLinked to original sources
bioRxiv2022

Antibody optimization enabled by artificial intelligence predictions of binding affinity and naturalness

Traditional antibody optimization approaches involve screening a small subset of the available sequence space, often resulting in drug candidates with suboptimal binding affinity, developability or immunogenicity. Based on two distinct antibodies, we demonstrate that deep contextual language models trained on high-throughput affinity data can quantitatively predict binding of unseen antibody sequence variants. These variants span a KD range of three orders of magnitude over a large mutational space. Our models reveal strong epistatic effects, which highlight the need for intelligent screening approaches. In addition, we introduce the modeling of "naturalness", a metric that scores antibody variants for similarity to natural immunoglobulins. We show that naturalness is associated with measures of drug developability and immunogenicity, and that it can be optimized alongside binding affinity using a genetic algorithm. This approach promises to accelerate and improve antibody engineering, and may increase the success rate in developing novel antibody and related drug candidates.

bioinformatics↗
bioRxiv2019

Two distinct mechanisms of small molecule inhibition of LpxA acyltransferase essential for lipopolysaccharide biosynthesis

The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multidrug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA and compound 2 is an uncompetitive inhibitor targeting the LpxA-product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1, and was optimized using structural information to achieve improved antibacterial activity against wild type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme-product complexes in drug discovery.

biochemistry↗
bioRxiv2019

A VP2/3-derived peptide exhibits potent antiviral activity against BK and JC polyomaviruses by targeting a novel VP1 binding site

In pursuit of effective therapeutics for human polyomaviruses, we identified a peptide derived from the BK polyomavirus (BKV) minor structural proteins VP2/3 that is a potent inhibitor of BKV infection with no observable cellular toxicity. The thirteen amino acid peptide binds to major structural protein VP1 in a new location within the pore with a low nanomolar KD. Alanine scanning of the peptide identified three key residues, substitution of each of which results in [~]1000-fold loss of affinity with a concomitant reduction in antiviral activity. NMR spectroscopy and an X-ray structurally-guided model demonstrate specific binding of the peptide to the pore of the VP1 pentamer that constitutes the BKV capsid. Cell-based assays with the peptide demonstrate nanomolar inhibition of BKV infection and suggest that the peptide likely blocks the viral entry pathway between endocytosis and escape from the host cell ER. The peptide motif is highly conserved among the polyomavirus clade, and homologous peptides exhibit similar binding properties for JC polyomavirus and inhibit infection with similar potency to BKV in a model cell line. Substitutions within VP1 or VP2/3 residues involved in VP1-peptide interaction negatively impact viral infectivity, potentially indicating the peptide-binding site within the VP1 pore is relevant for VP1-VP2/3 interactions. The inhibitory potential of the peptide-binding site first reported here may present a novel target for development of new anti-polyomavirus therapies. In summary, we present the first anti-polyomavirus inhibitor that acts via a novel mechanism of action by specifically targeting the pore of VP1.

microbiology↗