Discovery of highly potent and ALK2/ALK1 selective kinase inhibitors using DNA-encoded chemistry technology.

Activin receptor type 1 (ACVR1; ALK2) and activin receptor like type 1 (ACVRL1; ALK1) are transforming growth factor beta family receptors that integrate extracellular signals of bone morphogenic proteins (BMPs) and activins into Mothers Against Decapentaplegic homolog 1/5 (SMAD1/SMAD5) signaling complexes. Several activating mutations in ALK2 are implicated in fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine gliomas, and ependymomas. The ALK2 R206H mutation is also present in a subset of endometrial tumors, melanomas, non-small lung cancers, and colorectal cancers, and ALK2 expression is elevated in pancreatic cancer.

Synthesis and Optimization of Small Molecule Inhibitors of Prostate Specific Antigen.

Semen liquefaction is a postejaculation process that transforms semen from a gel-like (coagulated) form to a water-like consistency (liquefied). This process is primarily regulated by serine proteases from the prostate gland, most prominently, prostate-specific antigen (PSA; KLK3). Inhibiting PSA activity has the potential to impede liquefaction of human semen, presenting a promising target for nonhormonal contraception in the female reproductive tract.

Reversible male contraception by targeted inhibition of serine/threonine kinase 33.

Men or mice with homozygous serine/threonine kinase 33 () mutations are sterile owing to defective sperm morphology and motility. To chemically evaluate STK33 for male contraception with STK33-specific inhibitors, we screened our multibillion-compound collection of DNA-encoded chemical libraries, uncovered potent STK33-specific inhibitors, determined the STK33 kinase domain structure bound with a truncated hit CDD-2211, and generated an optimized hit CDD-2807 that demonstrates nanomolar cellular potency (half-maximal inhibitory concentration = 9.2 nanomolar) and favorable metabolic stability.

DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors.

The development of SARS-CoV-2 main protease (M) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate M inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of M. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using M as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of M with low nanomolar K values.

Glycofullerene-AuNPs as multivalent ligands of DC-SIGN and bacterial lectin FimH: tuning nanoparticle size and ligand density.

Glycoclusters have been extensively investigated for their inhibition of multivalent carbohydrate-protein interactions, which is often the first step for bacterial and viral pathogens to selectively bind their host cells. Glycoclusters may thus prevent infections by blocking the microbe attachment onto the host cell surface. The potency of multivalent carbohydrate-protein interactions is largely derived from the spatial arrangement of the ligand and the nature and flexibility of the linker.

Multivalent 9-O-Acetylated-sialic acid glycoclusters as potent inhibitors for SARS-CoV-2 infection.

The recent emergence of highly transmissible SARS-CoV-2 variants illustrates the urgent need to better understand the molecular details of the virus binding to its host cell and to develop anti-viral strategies. While many studies focused on the role of the angiotensin-converting enzyme 2 receptor in the infection, others suggest the important role of cell attachment factors such as glycans. Here, we use atomic force microscopy to study these early binding events with the focus on the role of sialic acids (SA).

Pillar[5]arene-Based Polycationic Glyco[2]rotaxanes Designed as Antibiofilm Agents.

(P.A.) is a human pathogen belonging to the top priorities for the discovery of new therapeutic solutions.

DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 M inhibitors.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (M) without extensive and time-consuming medicinal chemistry.

Stereoselective synthesis of rapamycin fragment to build a macrocyclic toolbox.

A stereoselective synthesis of a rapamycin fragment is developed and further utilized toward building a macrocyclic chemical toolbox. The amino alcohol moiety embedded in the 22-membered macrocyclic ring allowed for the addition of a variation in the chiral side chain. The key reactions leading to the synthesis of the rapamycin-derived pyran fragment include the following: (i) Paterson aldol, (ii) stereoselective β-OH carbonyl reduction, and (iii) regio- and stereoselective intramolecular oxy-Michael reaction.

Practical stereoselective synthesis of eribulin fragment toward building a hybrid macrocyclic toolbox.

A practical stereoselective synthesis to obtain the substituted furan ring as the substructure of eribulin is developed. An asymmetric syn-aldol and intramolecular oxy-Michael were two key steps in our approach. The functionalized furan derivatives were then utilized further to build the 14- and 12-membered macrocyclic diversity as trans- and cis-fused (C-29 and C-30) compounds.

Selected hybrid natural products as tubulin modulators.

Modulators of microtubule dynamics have received increasing attention because of their potential to stop cancer growth. Although it belongs to the category of complex protein-protein interactions (PPIs), which are generally considered difficult to modulate through small molecules, the use of microtubule is considered a well-validated target. There are a number of bioactive natural products and related compounds that are currently in use as drugs or in clinical trials as next generation anti-cancer agents.