Deping Wang - Academia.edu (original) (raw)

Papers by Deping Wang

Research paper thumbnail of Identification of novel bifunctional HIV-1 reverse transcriptase inhibitors

Journal of Antimicrobial Chemotherapy, 2017

The increasing prevalence of mutations in HIV-1 reverse transcriptase (RT) that confer resistance... more The increasing prevalence of mutations in HIV-1 reverse transcriptase (RT) that confer resistance to existing NRTIs and NNRTIs underscores the need to develop RT inhibitors with novel mode-of-inhibition and distinct resistance profiles. Methods: Biochemical assays were employed to identify inhibitors of RT activity and characterize their mode of inhibition. The antiviral activity of the inhibitors was assessed by cell-based assays using laboratory HIV-1 isolates and MT4 cells. RT variants were purified via avidin affinity columns. Results: Compound A displayed equal or greater potency against many common NNRTI-resistant RTs (K103N and Y181C RTs) relative to WT RT. Despite possessing certain NNRTI-like properties, such as being unable to inhibit an engineered variant of RT lacking an NNRTI-binding pocket, we found that compound A was dependent on Mg 2! for binding to RT. Optimization of compound A led to more potent analogues, which retained similar activities against WT and K103N mutant viruses with submicromolar potency in a cell-based assay. One of the analogues, compound G, was crystallized in complex with RT and the structure was determined at 2.6 Å resolution. The structure indicated that compound G simultaneously interacts with the active site (Asp 186), the highly conserved primer grip region (Leu 234 and Trp 229) and the NNRTI-binding pocket (Tyr 188).

Research paper thumbnail of Antiviral drug design: computational analyses of the effects of the L100I mutation for HIV-RT on the binding of NNRTIs

Bioorganic & Medicinal Chemistry Letters, 2001

Monte Carlo/free energy perturbation (MC/FEP) calculations were used to evaluate the binding free... more Monte Carlo/free energy perturbation (MC/FEP) calculations were used to evaluate the binding free energy change for HIV-RT/inhibitor complexes upon L100I mutation. Inhibitor size and flexibility adjacent to hydrogen-bonding sites are evident as important considerations for antiviral drug design.

Research paper thumbnail of Validation of a Model for the Complex of HIV-1 Reverse Transcriptase with Nonnucleoside Inhibitor TMC125

Journal of the American Chemical Society, 2003

The binding of nonnucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (HIVRT) in a pock... more The binding of nonnucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (HIVRT) in a pocket proximal to the polymerase active site disrupts the enyzme's function. Many classes of NNRTIs have been identified, and three inhibitors (nevirapine, delavirdine, and efavirenz) have been approved for clinical treatment of HIV-1 infections. 1 However, the success of NNRTI-inclusive chemotherapy is compromised by the rapid emergence of resistant viral strains carrying mutations at residues that surround the NNRTI binding pocket. 2 Frequently selected single mutations in vivo are L100I, V106A, K103N, Y181C, and Y188C/L. Each effectively disables the approved NNRTIs except Y181C for efavirenz (Sustiva). Second generation NNRTIs including quinoxaline GW420867X, the imidazole derivative S-1153 (capravirine), the quinazolinones DPC961 and DPC083, and members of the ADAM, PETT, QXPT, and PBO series exhibit improved potency against many mutant HIVRT strains. 1 DPC083 and the diarylpyrimidine TMC125 appear particularly promising in phase II clinical trials. 3-5 TMC125 inhibits wild-type (WT) HIVRT, the common NNRTI-resistant single mutants, and the K103N/Y181C double mutant with below 10 nM potency. 4

Research paper thumbnail of Structural understanding of stabilization patterns in engineered bispecific Ig-like antibody molecules

Structural understanding of stabilization patterns in engineered bispecific Ig-like antibody molecules

Proteins: Structure, Function, and Bioinformatics, 2009

Bispecific immunoglobulin-like antibodies capable of engaging multiple antigens represent a promi... more Bispecific immunoglobulin-like antibodies capable of engaging multiple antigens represent a promising new class of therapeutic agents. Engineering of these molecules requires optimization of the molecular properties of one of the domain components. Here, we present a detailed crystallographic and computational characterization of the stabilization patterns in the lymphotoxin-beta receptor (LTbetaR) binding Fv domain of an anti-LTbetaR/anti-TNF-related apoptosis inducing ligand receptor-2 (TRAIL-R2) bispecific immunoglobulin-like antibody. We further describe a new hierarchical structure-guided approach toward engineering of antibody-like molecules to enhance their thermal and chemical stability.

Research paper thumbnail of Structure-guided design of antibodies

Structure-guided design of antibodies

… Computer-Aided Drug …, 2010

Monoclonal antibodies capable of recognizing antigens with high affinity and specificity represen... more Monoclonal antibodies capable of recognizing antigens with high affinity and specificity represent a well established class of biological agents. Since the development of hybridoma technology in 1975, advances in recombinant DNA technologies and computational and biophysical methods have allowed us to develop a better understanding of the relationships between antibody sequence, structure, and function. These advances enable us to manipulate antibody sequences with the goal of improving upon, or creating new biological or biophysical properties. In this review we will focus on recent successes in using structure-guided computational methods to design antibodies and antibody-like molecules with optimized affinity and specificity to antigen and for enhancing protein stability.

Research paper thumbnail of Structural understanding of stabilization patterns in engineered bispecific Ig-like antibody molecules

Structural understanding of stabilization patterns in engineered bispecific Ig-like antibody molecules

Proteins: Structure, Function, and Bioinformatics, 2009

Bispecific immunoglobulin-like antibodies capable of engaging multiple antigens represent a promi... more Bispecific immunoglobulin-like antibodies capable of engaging multiple antigens represent a promising new class of therapeutic agents. Engineering of these molecules requires optimization of the molecular properties of one of the domain components. Here, we present a detailed crystallographic and computational characterization of the stabilization patterns in the lymphotoxin-beta receptor (LTbetaR) binding Fv domain of an anti-LTbetaR/anti-TNF-related apoptosis inducing ligand receptor-2 (TRAIL-R2) bispecific immunoglobulin-like antibody. We further describe a new hierarchical structure-guided approach toward engineering of antibody-like molecules to enhance their thermal and chemical stability.

Research paper thumbnail of Identification of novel bifunctional HIV-1 reverse transcriptase inhibitors

Journal of Antimicrobial Chemotherapy, 2017

The increasing prevalence of mutations in HIV-1 reverse transcriptase (RT) that confer resistance... more The increasing prevalence of mutations in HIV-1 reverse transcriptase (RT) that confer resistance to existing NRTIs and NNRTIs underscores the need to develop RT inhibitors with novel mode-of-inhibition and distinct resistance profiles. Methods: Biochemical assays were employed to identify inhibitors of RT activity and characterize their mode of inhibition. The antiviral activity of the inhibitors was assessed by cell-based assays using laboratory HIV-1 isolates and MT4 cells. RT variants were purified via avidin affinity columns. Results: Compound A displayed equal or greater potency against many common NNRTI-resistant RTs (K103N and Y181C RTs) relative to WT RT. Despite possessing certain NNRTI-like properties, such as being unable to inhibit an engineered variant of RT lacking an NNRTI-binding pocket, we found that compound A was dependent on Mg 2! for binding to RT. Optimization of compound A led to more potent analogues, which retained similar activities against WT and K103N mutant viruses with submicromolar potency in a cell-based assay. One of the analogues, compound G, was crystallized in complex with RT and the structure was determined at 2.6 Å resolution. The structure indicated that compound G simultaneously interacts with the active site (Asp 186), the highly conserved primer grip region (Leu 234 and Trp 229) and the NNRTI-binding pocket (Tyr 188).

Research paper thumbnail of Antiviral drug design: computational analyses of the effects of the L100I mutation for HIV-RT on the binding of NNRTIs

Bioorganic & Medicinal Chemistry Letters, 2001

Monte Carlo/free energy perturbation (MC/FEP) calculations were used to evaluate the binding free... more Monte Carlo/free energy perturbation (MC/FEP) calculations were used to evaluate the binding free energy change for HIV-RT/inhibitor complexes upon L100I mutation. Inhibitor size and flexibility adjacent to hydrogen-bonding sites are evident as important considerations for antiviral drug design.

Research paper thumbnail of Validation of a Model for the Complex of HIV-1 Reverse Transcriptase with Nonnucleoside Inhibitor TMC125

Journal of the American Chemical Society, 2003

The binding of nonnucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (HIVRT) in a pock... more The binding of nonnucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (HIVRT) in a pocket proximal to the polymerase active site disrupts the enyzme's function. Many classes of NNRTIs have been identified, and three inhibitors (nevirapine, delavirdine, and efavirenz) have been approved for clinical treatment of HIV-1 infections. 1 However, the success of NNRTI-inclusive chemotherapy is compromised by the rapid emergence of resistant viral strains carrying mutations at residues that surround the NNRTI binding pocket. 2 Frequently selected single mutations in vivo are L100I, V106A, K103N, Y181C, and Y188C/L. Each effectively disables the approved NNRTIs except Y181C for efavirenz (Sustiva). Second generation NNRTIs including quinoxaline GW420867X, the imidazole derivative S-1153 (capravirine), the quinazolinones DPC961 and DPC083, and members of the ADAM, PETT, QXPT, and PBO series exhibit improved potency against many mutant HIVRT strains. 1 DPC083 and the diarylpyrimidine TMC125 appear particularly promising in phase II clinical trials. 3-5 TMC125 inhibits wild-type (WT) HIVRT, the common NNRTI-resistant single mutants, and the K103N/Y181C double mutant with below 10 nM potency. 4

Research paper thumbnail of Structural understanding of stabilization patterns in engineered bispecific Ig-like antibody molecules

Structural understanding of stabilization patterns in engineered bispecific Ig-like antibody molecules

Proteins: Structure, Function, and Bioinformatics, 2009

Bispecific immunoglobulin-like antibodies capable of engaging multiple antigens represent a promi... more Bispecific immunoglobulin-like antibodies capable of engaging multiple antigens represent a promising new class of therapeutic agents. Engineering of these molecules requires optimization of the molecular properties of one of the domain components. Here, we present a detailed crystallographic and computational characterization of the stabilization patterns in the lymphotoxin-beta receptor (LTbetaR) binding Fv domain of an anti-LTbetaR/anti-TNF-related apoptosis inducing ligand receptor-2 (TRAIL-R2) bispecific immunoglobulin-like antibody. We further describe a new hierarchical structure-guided approach toward engineering of antibody-like molecules to enhance their thermal and chemical stability.

Research paper thumbnail of Structure-guided design of antibodies

Structure-guided design of antibodies

… Computer-Aided Drug …, 2010

Monoclonal antibodies capable of recognizing antigens with high affinity and specificity represen... more Monoclonal antibodies capable of recognizing antigens with high affinity and specificity represent a well established class of biological agents. Since the development of hybridoma technology in 1975, advances in recombinant DNA technologies and computational and biophysical methods have allowed us to develop a better understanding of the relationships between antibody sequence, structure, and function. These advances enable us to manipulate antibody sequences with the goal of improving upon, or creating new biological or biophysical properties. In this review we will focus on recent successes in using structure-guided computational methods to design antibodies and antibody-like molecules with optimized affinity and specificity to antigen and for enhancing protein stability.

Research paper thumbnail of Structural understanding of stabilization patterns in engineered bispecific Ig-like antibody molecules

Structural understanding of stabilization patterns in engineered bispecific Ig-like antibody molecules

Proteins: Structure, Function, and Bioinformatics, 2009

Bispecific immunoglobulin-like antibodies capable of engaging multiple antigens represent a promi... more Bispecific immunoglobulin-like antibodies capable of engaging multiple antigens represent a promising new class of therapeutic agents. Engineering of these molecules requires optimization of the molecular properties of one of the domain components. Here, we present a detailed crystallographic and computational characterization of the stabilization patterns in the lymphotoxin-beta receptor (LTbetaR) binding Fv domain of an anti-LTbetaR/anti-TNF-related apoptosis inducing ligand receptor-2 (TRAIL-R2) bispecific immunoglobulin-like antibody. We further describe a new hierarchical structure-guided approach toward engineering of antibody-like molecules to enhance their thermal and chemical stability.