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Full-Text Articles in Life Sciences
Association Of A Novel Human Immunodeficiency Virus Type 1 Protease Substrate Cleft Mutation, L23i, With Protease Inhibitor Therapy And In Vitro Drug Resistance, Elizabeth Johnston, Mark Winters, Soo-Yon Rhee, Thomas Merigan, Celia Schiffer, Robert Shafer
Association Of A Novel Human Immunodeficiency Virus Type 1 Protease Substrate Cleft Mutation, L23i, With Protease Inhibitor Therapy And In Vitro Drug Resistance, Elizabeth Johnston, Mark Winters, Soo-Yon Rhee, Thomas Merigan, Celia Schiffer, Robert Shafer
Celia A. Schiffer
We observed a previously uncharacterized mutation in the protease substrate cleft, L23I, in 31 of 4,303 persons undergoing human immunodeficiency virus type 1 genotypic resistance testing. In combination with V82I, L23I was associated with a sevenfold reduction in nelfinavir susceptibility and a decrease in replication capacity. In combination with other drug resistance mutations, L23I was associated with multidrug resistance and a compensatory increase in replication capacity.
Toward The Design Of Mutation-Resistant Enzyme Inhibitors: Further Evaluation Of The Substrate Envelope Hypothesis, Visvaldas Kairys, Michael Gilson, Viney Lather, Celia Schiffer, Miguel Fernandes
Toward The Design Of Mutation-Resistant Enzyme Inhibitors: Further Evaluation Of The Substrate Envelope Hypothesis, Visvaldas Kairys, Michael Gilson, Viney Lather, Celia Schiffer, Miguel Fernandes
Celia A. Schiffer
Previous studies have shown the usefulness of the substrate envelope concept in the analysis and prediction of drug resistance profiles for human immunodeficiency virus protease mutants. This study tests its applicability to several other therapeutic targets: Abl kinase, chitinase, thymidylate synthase, dihydrofolate reductase, and neuraminidase. For the targets where many (> or =6) mutation data are available to compute the average mutation sensitivity of inhibitors, the total volume of an inhibitor molecule that projects outside the substrate envelope V(out), is found to correlate with average mutation sensitivity. Analysis of a locally computed volume suggests that the same correlation would hold …
Combating Susceptibility To Drug Resistance: Lessons From Hiv-1 Protease, Nancy King, Moses Prabu-Jeyabalan, Ellen Nalivaika, Celia Schiffer
Combating Susceptibility To Drug Resistance: Lessons From Hiv-1 Protease, Nancy King, Moses Prabu-Jeyabalan, Ellen Nalivaika, Celia Schiffer
Celia A. Schiffer
Drug resistance is a major obstacle in modern medicine. However, resistance is rarely considered in drug development and may inadvertently be facilitated, as many designed inhibitors contact residues that can mutate to confer resistance, without significantly impairing function. Contemporary drug design often ignores the detailed atomic basis for function and primarily focuses on disrupting the target's activity, which is necessary but not sufficient for developing a robust drug. In this study, we examine the impact of drug-resistant mutations in HIV-1 protease on substrate recognition and demonstrate that most primary active site mutations do not extensively contact substrates, but are critical …
Hiv-1 Protease Inhibitors From Inverse Design In The Substrate Envelope Exhibit Subnanomolar Binding To Drug-Resistant Variants, Michael Altman, Akbar Ali, G. S. Kiran Kumar Reddy, Madhavi Nalam, Saima Anjum, Hong Cao, Sripriya Chellappan, Visvaldas Kairys, Miguel Fernandes, Michael Gilson, Celia Schiffer, Tariq Rana, Bruce Tidor
Hiv-1 Protease Inhibitors From Inverse Design In The Substrate Envelope Exhibit Subnanomolar Binding To Drug-Resistant Variants, Michael Altman, Akbar Ali, G. S. Kiran Kumar Reddy, Madhavi Nalam, Saima Anjum, Hong Cao, Sripriya Chellappan, Visvaldas Kairys, Miguel Fernandes, Michael Gilson, Celia Schiffer, Tariq Rana, Bruce Tidor
Celia A. Schiffer
The acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the …
Human Immunodeficiency Virus Type 1 Protease-Correlated Cleavage Site Mutations Enhance Inhibitor Resistance, Madhavi Kolli, Eric Stawiski, Colombe Chappey, Celia Schiffer
Human Immunodeficiency Virus Type 1 Protease-Correlated Cleavage Site Mutations Enhance Inhibitor Resistance, Madhavi Kolli, Eric Stawiski, Colombe Chappey, Celia Schiffer
Celia A. Schiffer
Drug resistance is an important cause of antiretroviral therapy failure in human immunodeficiency virus (HIV)-infected patients. Mutations in the protease render the virus resistant to protease inhibitors (PIs). Gag cleavage sites also mutate, sometimes correlating with resistance mutations in the protease, but their contribution to resistance has not been systematically analyzed. The present study examines mutations in Gag cleavage sites that associate with protease mutations and the impact of these associations on drug susceptibilities. Significant associations were observed between mutations in the nucleocapsid-p1 (NC-p1) and p1-p6 cleavage sites and various PI resistance-associated mutations in the protease. Several patterns were frequently …