Design and synthesis of wm5 analogues as HIV-1 TAR RNA binders

The 6-aminoquinolone WM5, previously identified by us, is among the most selective small molecules known as TAR RNA binders to show anti-HIV activity. Methods: Starting from WM5, a series of analogues modified at N-1, C-6 or C-7 position was prepared by inserting guanidine or amidine groups as well as other protonable moieties intended to electrostatically bind the phosphate backbone of TAR. All the compounds were tested for their ability to inhibit HIV-1 replication in MT-4 cells and in parallel for their cytotoxicity. The active compounds were also evaluated for their ability to interfere with the formation of the Tat-TAR complex using a Fluorescence Quenching Assay (FQA). Results: Some of the synthesized compounds showed an anti-HIV-1 activity in the sub-micromolar range with the naphthyridone derivatives being the most potent. Three of the synthesized derivatives were able to interact with the Tat-TAR complex formation presenting Ki values improved as compared to the values obtained with WM5. Conclusion: The addition of a pyridine-based protonable side chain at the N-1 position of the quinolone/naphthyridone core imparted to the compounds the ability to interfere with Tat-TAR complex formation and HIV-1 replicatio

Broad-spectrum coronavirus 3C-like protease peptidomimetic inhibitors effectively block SARS-CoV-2 replication in cells: Design, synthesis, biological evaluation, and X-ray structure determination

Despite the approval of vaccines, monoclonal antibodies and restrictions during the pandemic, the demand for new efficacious and safe antivirals is compelling to boost the therapeutic arsenal against the COVID-19. The viral 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for replication with high homology in the active site across CoVs and variants showing an almost unique specificity for Leu-Gln as P2-P1 residues, allowing the development of broad-spectrum inhibitors.The design, synthesis, biological activity, and cocrystal structural information of newly conceived peptidomimetic covalent reversible inhibitors are herein described. The inhibitors display an aldehyde warhead, a Gln mimetic at P1 and modified P2-P3 residues. Particularly, functionalized proline residues were inserted at P2 to stabilize the beta-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CLpro of SARS-CoV-2 and MERS-CoV and inhibited viral replication of three human CoVs, i.e. SARS-CoV-2, MERS-CoV, and HCoV 229 in different cell lines. Particularly, derivative 12 exhibited nM-low mu M antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CLpro validating our design. Altogether, these results foster future work toward broad-spectrum 3CLpro inhibitors to challenge CoVs related pandemics

Influence of Periodontal Biotype on Root Surface Exposure During Orthodontic Treatment : a Preliminary Study

The aim of this study was to investigate the role of periodontal biotype in the development of gingival recession in patients who have undergone orthodontic treatment. A total of 60 mandibular incisors were analyzed. The qualitative assessment of periodontal biotype was performed with the use of a new biotype probe. A strong correlation was found between thin biotype and proinclination in terms of recession depth and keratinized tissue width. Patients with thin periodontal biotype are more prone to gingival margin instability, irrespective of the type of orthodontic movements. Thin periodontal biotype and proinclination orthodontic movement were related to loss of keratinized tissue width

Il monitoraggio biologico del cobalto quale metodo di misura per esposizioni professionali ed ambientali dicirca 4 mesi

Dati sulla cinetica del Co nel sangue in un gruppo di 32 lavoratori esposti attraverso il monitoraggio per 16 settimane consecutive degli addotti del cobalto alla globin

Targeting SARS-CoV-2 Proteases and Polymerase for COVID-19 Treatment: State of the Art and Future Opportunities

The newly emerged coronavirus, called SARS-CoV-2, is the causing pathogen of pandemic COVID-19. The identification of drugs to treat COVID-19 and other coronavirus diseases is an urgent global need, thus different strategies targeting either virus or host cell are still under investigation. Direct-acting agents, targeting protease and polymerase functionalities, represent a milestone in antiviral therapy. The 3C-like (or Main) protease (3CLpro) and the nsp12 RNA-dependent RNA-polymerase (RdRp) are the best characterized SARS-CoV-2 targets and show the highest degree of conservation across coronaviruses fostering the identification of broad-spectrum inhibitors. Coronaviruses also possess a papain-like protease, another essential enzyme, still poorly characterized and not equally conserved, limiting the identification of broad-spectrum agents. Herein, we provide an exhaustive comparative analysis of SARS-CoV-2 proteases and RdRp with respect to other coronavirus homologues. Moreover, we highlight the most promising inhibitors of these proteins reported so far, including the possible strategies for their further development

Visible-Light Photocatalytic Functionalization of Isocyanides for the Synthesis of Secondary Amides and Ketene Aminals

A new visible light-induced photocatalytic protocol enabling the formation of secondary amides from electron-poor organic bromides and isocyanides was developed. In addition, the in situ interception of ketenimine intermediates with nitrogen nucleophiles such as amines, hydrazines, and TMSN3 afforded, in a one-pot two-step procedure, valuable scaffolds such as ketene aminals, pyrazolones, and tetrazoles. Mechanistic evidence confirmed a radical pathway where isocyanides acted as radical geminal acceptors generating key imidoyl radical species

Visible light photocatalysis in the late-stage functionalization of pharmaceutically relevant compounds

The late stage functionalization (LSF) of complex biorelevant compounds is a powerful tool to speed up the identification of structure-Activity relationships (SARs) and to optimize ADME profiles. To this end, visible-light photocatalysis offers unique opportunities to achieve smooth and clean functionalization of drugs by unlocking site-specific reactivities under generally mild reaction conditions. This review offers a critical assessment of current literature, pointing out the recent developments in the field while emphasizing the expected future progress and potential applications. Along with paragraphs discussing the visible-light photocatalytic synthetic protocols so far available for LSF of drugs and drug candidates, useful and readily accessible synoptic tables of such transformations, divided by functional groups, will be provided, thus enabling a useful, fast, and easy reference to them

SARS-CoV-2 Entry Inhibitors: Small Molecules and Peptides Targeting Virus or Host Cells

The pandemic evolution of SARS-CoV-2 infection is forcing the scientific community to unprecedented efforts to explore all possible approaches against COVID-19. In this context, targeting virus entry is a promising antiviral strategy for controlling viral infections. The main strategies pursued to inhibit the viral entry are considering both the virus and the host factors involved in the process. Primarily, direct-acting antivirals rely on inhibition of the interaction between ACE2 and the receptor binding domain (RBD) of the Spike (S) protein or targeting the more conserved heptad repeats (HRs), involved in the membrane fusion process. The inhibition of host TMPRSS2 and cathepsins B/L may represent a complementary strategy to be investigated. In this review, we discuss the development entry inhibitors targeting the S protein, as well as the most promising host targeting strategies involving TMPRSS2 and CatB/L, which have been exploited so far against CoVs and other related viruses

Isocyanide chemistry enabled by continuous flow technology

Isocyanides are valuable compounds for organic synthesis. However, the poor stability and distressing odour have often limited their widespread applications in common laboratory practice and industrial setting. Herein, a continuous flow approach to enable the synthesis, purification and in-line multicomponent reaction of isocyanides, is presented