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The unique and complex structure of papain-like protease (PL pro ) of the SARS-CoV-2 virus represents a difficult challenge for antiviral development, yet it offers a compelling validated target for effective therapy of COVID-19. The surge in scientific interest in inhibiting this cysteine protease emerged after its demonstrated connection to the cytokine storm in patients with COVID-19 disease. Furthermore, the development of new inhibitors against PL pro may also be beneficial for the treatment of respiratory infections caused by emerging coronavirus variants of concern. This review article provides a comprehensive overview of PL pro inhibitors, focusing on the structural framework of the known inhibitor GRL0617 and its analogs. We categorize PL pro inhibitors on the basis of their structures and binding site: Glu167 containing site, BL2 groove, Val70 Ub site, and Cys111 containing catalytic site. We summarize and evaluate the majority of GRL0617-like inhibitors synthesized so far, highlighting their published biochemical parameters, which reflect their efficacy. Published research has shown that strategic modifications to GRL0617, such as decorating the naphthalene ring, extending the aromatic amino group or the orthomethyl group, can substantially decrease the IC 50 from micromolar up to nanomolar concentration range. Some advantageous modifications significantly enhance inhibitory activity, paving the way for the development of new potent compounds. Our review places special emphasis on structures that involve direct modifications to the GRL0617 scaffold, including piperidine carboxamides and modified benzylmethylnaphthylethanamines (Jun9 scaffold). All these compounds are believed to inhibit the proteolytic, deubiquitination, and deISGylation activity of PL pro , biochemical processes linked to the severe progression of COVID-19. Finally, we summarize the development efforts for SARS-CoV-2 PL pro inhibitors, in detailed structure-activity relationships diagrams. This aims to inform and inspire future research in the search for potent antiviral agents against PL pro of current and emerging coronavirus threats., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vladimir Frecer reports financial support was provided by Slovak Research and Development Agency, research grant APVV-21-0108. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Softwood bark is an important source for producing chemicals and materials as well as bioenergy. Extraction is regarded as a key technology for obtaining chemicals in general, and valorizing bark as a source of such chemicals in particular. In this paper, properties of 237 compounds identified in various studies dealing with extraction of softwood bark were described. Finally, some challenges and perspectives on the production of chemicals from bark are discussed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

New structurally simple indolic non peptidic HIV Protease inhibitors were synthesized from (S)-glycidol by regioselective methods. Following the concept of targeting the protein backbone, different substitution patterns were introduced onto the common stereodefined isopropanolamine core modifying the type of functional group on the indole, the position of the functional group on the indole and the type of the nitrogen containing group (sulfonamides or perhydroisoquinoline), alternatively. The systematic study on in vitro inhibition activity of such compounds confirmed the general beneficial effect of the 5-indolyl substituents in presence of arylsulfonamide moieties, which furnished activities in the micromolar range. Preliminary docking analysis allowed to identify several key features of the binding mode of such compounds to the protease., (Copyright © 2014. Published by Elsevier Ltd.)

We report the synthesis of 5'-modified thymidines (16, 18, 21, 23) and 5,5'-bis-substituted 2'-deoxyuridine analogues (30, 47) as inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt). These analogues were evaluated for their capacity to inhibit TMPKmt and solely two 5'-modified thymidines were found to possess moderate inhibitory activity. In addition, a feasibility study of protecting groups for the 5-CH(2)OH moiety of 2'-deoxyuridines is described that enables to introduce the desired 5'-modification., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Evidences of oseltamivir resistant influenza patients raised the need of novel neuraminidase inhibitors. In this study, five oseltamivir analogs PMC-31-PMC-36, synthesised according to the outcomes of a rational design analysis aimed to investigate the effects of substitution at the 5-amino and 4-amido groups of oseltamivir on its antiviral activity, were screened for their inhibition against neuraminidase N1 and N3. The enzymes used as models were from the avian influenza A H7N1 and H7N3 viruses. The neuraminidase inhibition assay was carried out by using recombinant species obtained from a baculovirus expression system and the fluorogenic substrate MUNANA. The assay was validated by using oseltamivir carboxylate as a reference inhibitor. Among the tested compounds, PMC-36 showed the highest inhibition on N1 with an IC(50) of 14.6±3.0nM (oseltamivir 25±4nM), while PMC-35 showed a significant inhibitory effect on N3 with an IC(50) of 0.1±0.03nM (oseltamivir 0.2±0.02nM). The analysis of the inhibitory properties of this panel of compounds allowed a preliminary assessment of a structure-activity relationship for the modification of the 4-amido and 5-amino groups of oseltamivir carboxylate. The substitution of the acetamido group in the oseltamivir structure with a 2-butenylamido moiety reduced the observed activity, while the introduction of a propenylamido group was well tolerated. Substitution of the free 5-amino group of oseltamivir carboxylate with an azide, decreased the activity against both N1 and N3. When these structural changes were both introduced, a dramatic reduction of activity was observed for both N1 and N3. The alkylation of the free 5-amino group in oseltamivir carboxylate introducing an isopropyl group seemed to increase the inhibitory effect for both N1 and N3 neuraminidases, displaying a more pronounced effect against N1., (Copyright © 2012. Published by Elsevier Ltd.)

In this paper we quantitatively analyse antimicrobial and haemolytic activities of porcine protegrin-1 (PG-1) mimetics-cyclic cationic peptides with beta-hairpin fold synthesised by Robinson et al. [Bioorg. Med. Chem.2005, 13, 2055]. The presented QSAR models, which use molecular properties related to possible mechanisms of cell membrane disruption that can be easily calculated from available data on amino acids, rationalize the relationships between sequences and antimicrobial and haemolytic potencies of the cyclic peptides. The best models obtained by application of genetic function approximation algorithm correlate antimicrobial potencies to the peptide's charge and amphipathicity index, while the haemolytic effect correlates well with the lipophilicity of residues forming the nonpolar face of the beta-hairpin. The models permit selection of site-directed residue substitutions leading to simultaneous optimization of antimicrobial and haemolytic potencies. Examples of such residue substitutions in the nonpolar face of a symmetric cyclic beta-hairpin PG-1 analogue with an ideal amphipathic structure are given.

The aspartic protease (PR) of the human immunodeficiency virus type 1 (HIV-1) is an important target for the design of specific antiviral agents dedicated to treatment of HIV-1 infection. We have employed computer-assisted combinatorial chemistry methods to design a small focused virtual library of nonsymmetrically substituted cyclic urea inhibitors of the PR. Nonsymmetrical compounds with decreased peptidic character were namely found to inhibit the PR with comparable inhibition potencies as their C2-pseudosymmetric counterparts and to possess superior pharmacokinetic properties. To generate the virtual library of fully nonsymmetrical cyclic urea analogs, diverse reagents were selected from databases of available chemicals with characteristics similar to those of the building blocks of known potent PR inhibitors. The X-ray structure of the protease-inhibitor complex PR-XV-638 was used as the receptor model in the structure-based focusing and in silico screening of the virtual library. A target-specific LUDI-type scoring function, parameterized for a QSAR training set of known cyclic urea inhibitors and validated on a set of compounds not included into the training set, was used to predict the inhibition constants (Ki) of the generated analogs toward the HIV-1 PR. The fragments most frequently occurring in the analogs with the highest predicted inhibition potencies (Ki*<10 pM) were then selected to constitute a highly focused library subset containing novel nonsymmetrical cyclic ureas with predicted Ki*s 1 order of magnitude lower than the most potent known cyclic urea inhibitors. ADME properties calculated for the most promising analogs suggested that the cyclic ureas are endowed with a wide range of favorable pharmacokinetic properties, which may favor the discovery of a potent orally administrable antiviral drug.