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Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer Jul 2017

Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer

Celia A. Schiffer

The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and subtropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing of 8 of the 13 substrate cleavage sites by dengue virus NS2B/NS3 protease. With no available direct-acting antiviral targeting DENV, NS2/NS3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds. However, the prime side also significantly modulates DENV protease binding affinity, as revealed by engineering the binding loop of aprotinin, a ...


Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer Jun 2017

Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer

Celia A. Schiffer

Molecular recognition is a highly interdependent process. Subsite couplings within the active site of proteases are most often revealed through conditional amino acid preferences in substrate recognition. However, the potential effect of these couplings on inhibition and thus inhibitor design is largely unexplored. The present study examines the interdependency of subsites in HIV-1 protease using a focused library of protease inhibitors, to aid in future inhibitor design. Previously a series of darunavir (DRV) analogs was designed to systematically probe the S1' and S2' subsites. Co-crystal structures of these analogs with HIV-1 protease provide the ideal opportunity to probe subsite interdependency ...


Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer May 2017

Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer

University of Massachusetts Medical School Faculty Publications

Molecular recognition is a highly interdependent process. Subsite couplings within the active site of proteases are most often revealed through conditional amino acid preferences in substrate recognition. However, the potential effect of these couplings on inhibition and thus inhibitor design is largely unexplored. The present study examines the interdependency of subsites in HIV-1 protease using a focused library of protease inhibitors, to aid in future inhibitor design. Previously a series of darunavir (DRV) analogs was designed to systematically probe the S1' and S2' subsites. Co-crystal structures of these analogs with HIV-1 protease provide the ideal opportunity to probe subsite interdependency ...


Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer Apr 2017

Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer

University of Massachusetts Medical School Faculty Publications

The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and subtropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing of 8 of the 13 substrate cleavage sites by dengue virus NS2B/NS3 protease. With no available direct-acting antiviral targeting DENV, NS2/NS3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds. However, the prime side also significantly modulates DENV protease binding affinity, as revealed by engineering the binding loop of aprotinin, a ...


Structure-Based Design Of Inhibitors Targeting Influenza A Virus M2 Proton Channel (A/M2), Jun Wang Dec 2010

Structure-Based Design Of Inhibitors Targeting Influenza A Virus M2 Proton Channel (A/M2), Jun Wang

Publicly Accessible Penn Dissertations

Influenza A virus M2 (A/M2) forms a homotetrameric channel in viral membranes that is highly selective for protons. A/M2 has been extensively studied by electrophysiologists, biophysicists, structural biologists and biochemists in order to understand the mechanism and selectivity of proton conductance from the structural basis. Medicinal chemists have also studied A/M2 as therapeutic target for anti-flu drugs. However, research on A/M2 drug binding lead to entirely different binding sites of two very similar anti-flu drugs. In light of the urgency in developing novel antivirals against drug resistant A/M2 mutants, it is imperative to solve this ...