Forty-four fragments were selected based on their mode of interaction. or sanglifehrin A, have disadvantages, including their size, potential for side effects unrelated to cyclophilin inhibition and drugCdrug interactions, unclear antiviral spectrum and manufacturing issues. Here we use a fragment-based drug discovery approach using nucleic magnetic resonance, X-ray crystallography and structure-based compound optimization to generate a new family of non-peptidic, small-molecule cyclophilin inhibitors with potent PPIase inhibitory activity and antiviral activity against hepatitis C virus, human immunodeficiency virus and coronaviruses. This family of compounds has the potential for broad-spectrum, high-barrier-to-resistance treatment of viral infections. Over the past decades, an increasing number of viruses causing unexpected illnesses and epidemics among humans, wildlife and livestock has emerged. These outbreaks have seriously stretched local and national resources in the economically developed world, whereas the capacity to control emerging diseases remains Microtubule inhibitor 1 limited in poorer regions where many of them have their origin. A number of virus-specific antiviral agents have been developed and commercialized since the early 1980s. These agents, including drugs that specifically inhibit members of the family, influenza viruses, human immunodeficiency virus (HIV), hepatitis B virus (HBV) and, more recently, hepatitis C virus (HCV), had a major medical impact1. However, the development costs of specific antiviral agents are Microtubule inhibitor 1 extremely high and there are many other medically important viral infections that require efficacious therapies. Thus, there is an urgent need for new families of broad-spectrum antiviral agents, that is, antiviral agents that are active against a number of different viral families2. Such compounds should target mechanisms common to different families of viruses, such as cellular components and/or functions involved in their life cycles. The cellular proteins cyclophilins have been shown to play a key role in the life cycle of Microtubule inhibitor 1 a number of different viral families. In addition, cyclophilin inhibitors were reported to inhibit the replication of different viruses, both and isomerases (PPIase) that catalyse the interconversion of the two energetically preferred conformers (and effectiveness against HIV, HCV and HBV replication3. A CsA analogue, alisporivir, showed potent anti-HCV activity PPIase inhibitory activity and antiviral activity against several families of viruses responsible for frequent human infections. Results Fragment screening In total, Rabbit Polyclonal to OR4A15 34,409 fragments were computationally docked into the canonical active site and the gatekeeper pocket of CypD by means of the FlexX programme. Forty-four fragments were selected based on their mode of interaction. Their ability to interact with CypD was further studied by means of NMR spectroscopy. Ten fragment hits with low-affinity dissociation constants (millimolar range) were identified (Supplementary Fig. 1). Their scaffolds and proline-mimicking motifs were used to select a set of 52 derivative fragments for subsequent X-ray crystallographic experiments. Apo CypD crystals were soaked with each of the 52 fragments. X-ray structures of CypD complexed with 14 fragments were obtained. Supplementary Fig. 2 shows the chemical structures of the 14 binding fragments. Four fragments (9, 11, 12 and 13) bound the catalytic site of CypD, whereas five fragments (6, 15, 16, 17 and 18) bound the gatekeeper pocket. Fragment 14 bound between the two sites. Finally, four fragments (5, 19, 20 and 21) were nonspecific multibinders. The density map of each fragment is shown in Supplementary Fig. 3 and at (https://figshare.com/articles/Stereo_views_of_cocrystal_structures_of_cyclophilin_inhibitors_with_cyclophilin_D/3490493). The ability of each fragment to inhibit cyclophilin activity was assessed in cell-free enzyme assays for CypA, CypB and CypD. The half-maximal inhibitory concentrations (IC50) of the 14 fragments were 5?mM in all instances. Fragment selection for linking Among the 14 fragment hits, the final selection of compounds 6 and 13 for subsequent compound optimization was based on a number of criteria, including their ligand efficiency, their ability to access key.
Forty-four fragments were selected based on their mode of interaction
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