Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection.

Magnus Hansson; Steven James Moss; Michael Bobardt; Udayan Chatterji; Nigel Coates; Jose A Garcia-Rivera; Eskil Elmer; Steve Kendrew; Pieter Leyssen; Johan Neyts; Mohammad Nur-E-Alam; Tony Warneck; Barrie Wilkinson; Philippe Gallay; Matthew Alan Gregory

doi:10.1016/j.chembiol.2014.10.023

Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection.

Magnus Hansson, Steven James Moss, Michael Bobardt, Udayan Chatterji, Nigel Coates, Jose A Garcia-Rivera, Eskil Elmer, Steve Kendrew, Pieter Leyssen, Johan Neyts, Mohammad Nur-E-Alam, Tony Warneck, Barrie Wilkinson, Philippe Gallay, Matthew Alan Gregory

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Abstract

Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products, which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed nonribosomal peptide/polyketide origin, to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of hepatitis B virus, hepatitis C virus (HCV), and HIV-1 replication, shows minimal inhibition of major drug transporters, and has a high barrier to generation of both HCV and HIV-1 resistance.

Original language	English
Pages (from-to)	285-292
Journal	Chemistry and Biology
Volume	22
Issue number	2
DOIs	https://doi.org/10.1016/j.chembiol.2014.10.023
Publication status	Published - 2015

Subject classification (UKÄ)

Respiratory Medicine and Allergy
Neurology
Cardiac and Cardiovascular Systems

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10.1016/j.chembiol.2014.10.023

Cell_Press__Hansson_e_al

http://www.ncbi.nlm.nih.gov/pubmed/25619934?dopt=Abstract

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Hansson, M., Moss, S. J., Bobardt, M., Chatterji, U., Coates, N., Garcia-Rivera, J. A., Elmer, E., Kendrew, S., Leyssen, P., Neyts, J., Nur-E-Alam, M., Warneck, T., Wilkinson, B., Gallay, P., & Gregory, M. A. (2015). Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection. Chemistry and Biology, 22(2), 285-292. https://doi.org/10.1016/j.chembiol.2014.10.023

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title = "Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection.",

abstract = "Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products, which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed nonribosomal peptide/polyketide origin, to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of hepatitis B virus, hepatitis C virus (HCV), and HIV-1 replication, shows minimal inhibition of major drug transporters, and has a high barrier to generation of both HCV and HIV-1 resistance.",

author = "Magnus Hansson and Moss, {Steven James} and Michael Bobardt and Udayan Chatterji and Nigel Coates and Garcia-Rivera, {Jose A} and Eskil Elmer and Steve Kendrew and Pieter Leyssen and Johan Neyts and Mohammad Nur-E-Alam and Tony Warneck and Barrie Wilkinson and Philippe Gallay and Gregory, {Matthew Alan}",

year = "2015",

doi = "10.1016/j.chembiol.2014.10.023",

language = "English",

volume = "22",

pages = "285--292",

journal = "Chemistry and Biology",

issn = "1879-1301",

publisher = "Cell Press",

number = "2",

}

Hansson, M, Moss, SJ, Bobardt, M, Chatterji, U, Coates, N, Garcia-Rivera, JA, Elmer, E, Kendrew, S, Leyssen, P, Neyts, J, Nur-E-Alam, M, Warneck, T, Wilkinson, B, Gallay, P & Gregory, MA 2015, 'Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection.', Chemistry and Biology, vol. 22, no. 2, pp. 285-292. https://doi.org/10.1016/j.chembiol.2014.10.023

TY - JOUR

T1 - Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection.

AU - Hansson, Magnus

AU - Moss, Steven James

AU - Bobardt, Michael

AU - Chatterji, Udayan

AU - Coates, Nigel

AU - Garcia-Rivera, Jose A

AU - Elmer, Eskil

AU - Kendrew, Steve

AU - Leyssen, Pieter

AU - Neyts, Johan

AU - Nur-E-Alam, Mohammad

AU - Warneck, Tony

AU - Wilkinson, Barrie

AU - Gallay, Philippe

AU - Gregory, Matthew Alan

PY - 2015

Y1 - 2015

N2 - Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products, which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed nonribosomal peptide/polyketide origin, to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of hepatitis B virus, hepatitis C virus (HCV), and HIV-1 replication, shows minimal inhibition of major drug transporters, and has a high barrier to generation of both HCV and HIV-1 resistance.

AB - Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products, which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed nonribosomal peptide/polyketide origin, to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of hepatitis B virus, hepatitis C virus (HCV), and HIV-1 replication, shows minimal inhibition of major drug transporters, and has a high barrier to generation of both HCV and HIV-1 resistance.

U2 - 10.1016/j.chembiol.2014.10.023

DO - 10.1016/j.chembiol.2014.10.023

M3 - Article

C2 - 25619934

SN - 1879-1301

VL - 22

SP - 285

EP - 292

JO - Chemistry and Biology

JF - Chemistry and Biology

IS - 2

ER -

Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection.

Abstract

Subject classification (UKÄ)

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