Coronavirus disease-19, caused by the novel β-coronavirus SARS-CoV-2, has created a global pandemic unseen in a century. Rapid worldwide efforts have enabled the characterization of the virus and its pathogenic mechanism. An early key finding is that SARS-CoV-2 uses spike proteins, the virus' most exposed structures, to bind to human ACE2 receptors and initiate cell invasion. Competitive targeting of the spike protein is a promising strategy to neutralize virus infectivity. This review article summarizes the discovery, binding modes and eventual applications of several classes of (bio)molecules targeting the spike protein: antibodies, nanobodies, soluble ACE2 variants, miniproteins, peptides and small molecules.
WHO has declared COVID-19 a pandemic, which has affected the whole world and has caused unprecedented social and economic disruption. Since the emergence of the disease, several druggable targets have been suggested including 3-chymotrypsin-like protease (3CLpro), spike, RNA-dependent RNA polymerase (RdRp), and the papain-like protease (PLpro) computational approach. From the beginning, viral replication has been the main focus for any antiviral drug development for viral diseases, including HCV, influenza virus, zika virus, norovirus, measles, dengue virus, and coronaviruses. This review lists the nucleoside, nucleotide, and non-nucleoside RdRp inhibitor analogues of various viral diseases that may be evaluated for drug development to treat COVID-19.
The rapid growth of COVID-19 cases is causing an increasing death toll and also paralyzing the world economy De novo drug discovery takes years to move from idea and/or pre-clinic to market, and it is not a short-term solution for the current SARS-CoV-2 pandemic Drug repurposing is perhaps the only short-term solution, while vaccination is a middle-term solution Here, we describe the discovery path of the HCV NS3–4A protease inhibitors boceprevir and telaprevir as SARS-CoV-2 main protease (3CLpro) inhibitors Based on our hypothesis that α-ketoamide drugs can covalently bind to the active site cysteine of the SARS-CoV-2 3CLpro, we performed docking studies, enzyme inhibition and co-crystal structure analyses and finally established that boceprevir, but not telaprevir, inhibits replication of SARS-CoV-2 and mouse hepatitis virus (MHV), another coronavirus, in cell culture Based on our studies, the HCV drug boceprevir deserves further attention as a repurposed drug for COVID-19 and potentially other coronaviral infections as well
In December 2019, an infectious disease was detected in Wuhan, China, caused by a new pathogenic coronavirus, named SARS-CoV-2 It spread very rapidly, and on March 11th of 2020, the outbreak was declared a pandemic by the World Health Organization Currently, effective treatment options remain limited SARS-CoV-2 enzyme main protease (MPRO) plays a pivotal role in the viral life cycle, making it a putative drug target In order to identify suitable hits to develop inhibitors with adequate antiviral properties, we explored the LASSBio Chemical Library employing multiple strategies of virtual screening A fragment-based pharmacophore model enabled the identification of key interactions involved in the molecular recognition at the catalytic site of MPRO, namely, with amino acid residues His41, His163 and Glu166 Docking-based virtual screening was performed, leading to the identification of LASSBio-1945 (9), a new hit of MPRO, presenting an IC50 = 15 97 μM This compound, an 1,3-benzodioxolyl sulfonamide, represents an interesting starting point for subsequent hit-to-lead optimization steps and, to the best of our knowledge, a new distinct chemotype for MPRO inhibition
New tridecaptin analogues are cheaper to make and retain strong Gram-negative activity.
TamA is the enzyme that controls the acyl chain length of the tambjamine natural products. Here we show that the catalytic ANL domain of TamA can be used to prepare a range of N-acyl amides.
Brazilian legumes and algae contain potent antiviral lectins.
Structure–activity relationship and crystallographic studies on HIF prolyl hydroxylase inhibitors reveal spiro[4.5]decanones as useful templates for generation of potent and selective 2OG oxygenase inhibitors.
Compounds 1 and 2 disrupt M. tuberculosis membrane potential and demonstrate bactericidal activity against non-replicating M. tuberculosis in pH 4.5 buffer.
Fluorescent probes derived from the fluoroquinolone antibiotic ciprofloxacin were synthesised using a Cu(i)-catalysed azide–alkyne cycloaddition (CuAAC) to link a ciprofloxacin azide derivative with alkyne-substituted green and blue fluorophores.
This paper describes the synthesis of the well-defined lipoarabinomannan (LAM) specific dodecasaccharide–protein conjugate and immunological studies.
Berberine is a bioactive alkaloid used in Chinese medicine and has numerous positive effects on biological systems.
Demonstration of FgaPT2 catalyzed alkyl-diversification of indole containing natural products.
Correction for ‘Targeting Brd4 for cancer therapy: inhibitors and degraders’ by Yingchao Duan et al., Med. Chem. Commun., 2018, 9, 1779–1802.
Correction for ‘Polyhydroxyalkanoates as biomaterials’ by Bhagyashri S. Thorat Gadgil et al., Med. Chem. Commun., 2017, 8, 1774–1787.
Influenza A virus is an enveloped negative single-stranded RNA virus that causes febrile respiratory infection and represents a clinically challenging threat to human health and even lives worldwide. Even more alarming is the emergence of highly pathogenic avian influenza (HPAI) strains such as H5N1, which possess much higher mortality rate (60%) than seasonal influenza strains in human infection. In this study, a novel series of heteroaromatic-based benzenesulfonamide derivatives were identified as M2 proton channel inhibitors. A systematic investigation of the structure-activity relationships and a molecular docking study demonstrated that the sulfonamide moiety and 2,5-dimethyl-substituted thiophene as the core structure played significant roles in the anti-influenza activity. Among the derivatives, compound 11k exhibited excellent antiviral activity against H5N1 virus with an EC50 value of 0.47 μM and selectivity index of 119.9, which are comparable to those of the reference drug amantadine.
Currently, IgG-binding peptides are widely utilized as a research tool, as molecules that guide substrates to the Fc site for site-selective antibody modification, leading to preparation of a homogeneous antibody-drug conjugate. In this study, a structure-activity relationship study of an IgG-binding peptide, 15-IgBP, that is focused on its C-terminal His residue was performed in an attempt to create more potent peptides. A peptide with a substitution of His17 by 2-pyridylalanine (2-Pya) showed a good binding affinity (15-His17(2-Pya), K d = 75.7 nM). In combination with a previous result, we obtained 15-Lys8Leu/His17(2-Pya)-OH that showed a potent binding affinity (K d = 2.48 nM) and avoided three synthetic problems concerning the p-hydroxybenzyl amidation at the C-terminus, the difficulty associated with coupling at the His7 position and the racemization of 2-Pya.
The quinolone antibiotics arose in the early 1960s, with the first examples possessing a narrow-spectrum activity with unfavorable pharmacokinetic properties.
An increasing focus on complex biology to cure diseases rather than merely treat symptoms has transformed how drug discovery can be approached. Instead of activating or blocking protein function, a growing repertoire of drug modalities can be leveraged or engineered to hijack cellular processes, such as translational regulation or degradation mechanisms. Drug hunters can therefore access a wider arsenal of modes-of-action to modulate biological processes and this review summarises these emerging strategies by highlighting the most representative examples of these approaches.
Polyketide natural products possess diverse biological activities including antibiotic, anticancer, and immunosuppressive. Their equally varied and complex structures arise from head-to-tail condensation of simple carboxyacyl monomers. Since the seminal discovery that biosynthesis of polyketides such as the macrolide erythromycin is catalyzed by uncharacteristically large, multifunctional enzymes, termed modular type I polyketide synthases, chemists and biologists alike have been inspired to harness the apparent modularity of the synthases to further diversify polyketide structures. Yet, initial attempts to perform "combinatorial biosynthesis" failed due to challenges associated with maintaining the structural and catalytic integrity of large, chimeric synthases. Fast forward nearly 30 years, and advancements in our understanding of polyketide synthase structure and function have allowed the field to make significant progress toward effecting desired modifications to polyketide scaffolds in addition to engineering small, chiral fragments. This review highlights selected examples of polyketide diversification via control of monomer selection, oxidation state, stereochemistry, and cyclization. We conclude with a perspective on the present and future of polyketide structure diversification and hope that the examples presented here will encourage medicinal chemists to embrace polyketide synthetic biology as a means to revitalize polyketide drug discovery.
