Unexpected small molecules as novel SIRT2 suicide inhibitors.

A series of sirtuin inhibitor candidates were assembled based on an intermediate ester (1a) our accidently discovered. After screening and evaluation, several SIRT2 selective inhibitors were identified, which can inhibit all the deacetylation, defatty-acylation and debenzoylation of SIRT2. Among these inhibitors, compound 1e was the best SIRT2 selective inhibitors. The primary study on the inhibitory mechanism indicated that compound 1e may be a suicide inhibitor acting as an irreversible way. Given almost all reported sirtuin inhibitors are non-covalent, sirtuin covalent inhibitors are still need to be developed. These findings will facilitate for further development of SIRT2 selective and suicide inhibitors.

Synthesis of Fucose Derivatives with Thiol Motifs towards Suicide Inhibition of Helicobacter pylori.

The syntheses of six thiol-exhibiting monosaccharides towards suicide inhibition of Helicobacter pylori are reported. Blood group Antigen Binding Adhesin (BabA), a bacterial membrane-bound lectin, binds to human ABO and Lewis b blood group structures displayed on the surface of host epithelial cells. Crystal structures of the carbohydrate-recognition domain revealed a conserved disulfide bonded loop that anchors a critical fucose residue in these blood group structures. Disruption of this loop by N-acetylcysteine results in reduced BabA-mediated adherence to human gastric tissue sections and attenuated virulence in Lewis b-expressing transgenic mice. With a view of creating specific inhibitors of the lectin, we designed and successfully synthesised six fucose-derived compounds with thiol motifs to engage in a thiol-disulfide exchange with this disulfide bond of BabA and form a glycan-lectin disulfide linkage. Branching and extending the fucose backbone with 2- and 3-carbon thiol motifs delivered a range of candidates to be tested for biological activity against BabA.

Discovery of Strecker-type α-aminonitriles as a new class of human carbonic anhydrase inhibitors using differential scanning fluorimetry.

A new type of carbonic anhydrase inhibitors was identified via differential scanning fluorimetry (DSF) screening. The compounds displayed interesting inhibition profile against human carbonic anhydrase isoforms I, II, IX and XII with an obvious selectivity displayed by one compound toward carbonic anhydrase (CA) IX, an established anti-cancer target. A hypothetical mechanism of inhibitory action by the Strecker-type α-aminonitriles has been proposed.

In-silico guided design, screening, and molecular dynamic simulation studies for the identification of potential SARS-CoV-2 main protease inhibitors for the targeted treatment of COVID-19.

COVID-19, the disease responsible for the recent pandemic, is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main protease (Mpro) of SARS-CoV-2 is an essential proteolytic enzyme that plays a number of important roles in the replication of the virus in human host cells. Blocking the function of SARS-CoV-2 Mpro offers a promising and targeted, therapeutic option for the treatment of the COVID-19 infection. Such an inhibitory strategy is currently successful in treating COVID-19 under FDA's emergency use authorization, although with limited benefit to the immunocompromised along with an unfortunate number of side effects and drug-drug interactions. Current COVID vaccines protect against severe disease and death but are mostly ineffective toward long COVID which has been seen in 5-36% of patients. SARS-CoV-2 is a rapidly mutating virus and is here to stay endemically. Hence, alternate therapeutics to treat SARS-CoV-2 infections are still needed. Moreover, because of the high degree of conservation of Mpro among different coronaviruses, any newly developed antiviral agents should better prepare us for potential future epidemics or pandemics. In this paper, we first describe the design and computational docking of a library of novel 188 first-generation peptidomimetic protease inhibitors using various electrophilic warheads with aza-peptide epoxides, α-ketoesters, and ß-diketones identified as the most effective. Second-generation designs, 192 compounds in total, focused on aza-peptide epoxides with drug-like properties, incorporating dipeptidyl backbones and heterocyclic ring motifs such as proline, indole, and pyrrole groups, yielding 8 hit candidates. These novel and specific inhibitors for SARS-CoV-2 Mpro can ultimately serve as valuable alternate and broad-spectrum antivirals against COVID-19.Communicated by Ramaswamy H. Sarma.

The art of suicidal molecular seduction for targeting drug resistance.

The development of drug resistance is one of the most significant challenges of the current century in the pharmaceutical industry. Superinfections, cancer chemoresistance, and resistance observed in many non-infectious diseases are nullifying the efforts and monetary supplies, put in the advent of new drug molecules. Millions of people die because of this drug resistance developed gradually through extensive use of the drugs. Inherently, some drugs are less prone to become ineffective by drug resistance than others. Covalent inhibitors bind to their targets via a biologically permanent bound with their cognate receptor and therefore display more potent inhibiting characteristics. Suicide inhibitors or mechanism-based inhibitors are one of the covalent inhibitors, which require a pre-activation step by their targeting enzyme. This step accrues their selectivity and specificity with respect to other covalent inhibitors. After that pre-activation step, they produce an analogue of the transition state of the catalytic enzyme, which is practically incapable of dissociating from the enzyme. Suicide inhibitors, due to their high intrinsic affinity toward the related enzyme, are resistant to many mechanisms involved in the development of drug resistance and can be regarded as one of the enemies of this scientific hurdle. These inhibitors compete even with monoclonal antibodies in terms of their cost-effectiveness and efficacy.

DESIGN AND SYNTHESIS OF DIBENZYLFURAN BASED ETHER AND ESTER DERIVATIVES AS POTENTIAL P450 INHIBITORS.

Cytochrome P450 enzymes are a superfamily of hemoproteins involved in the metabolism and detoxification of endogenous and exogenous compounds. P450s are involved in the bioactivation of certain procarcinogens leading to the production of carcinogenic species. This has resulted in P450s' popularity as targets in cancer research. Developing selective and potent mechanism-based inhibitors for these enzymes is expected to be the key to understanding their mechanisms of action, as well as, developing potential anticancer agents. Our group has shown that certain aryl and aryl-alkyl acetylenes act as inhibitors of these enzymes. In an attempt to increase the number of selective P450 inhibitors available for enzymatic studies, five novel dibenzofuran ethers and esters have been designed and synthesized successfully.