Antiviral inhibitors of HIV-1 protease are a notable success structure-based drug design and have dramatically improved AIDS therapy. Analysis the structures activities resistant variants has revealed novel molecular mechanisms resistance guided tight-binding for variants. The plethora reveals distinct associated with resistance: mutations that alter interactions or substrates; dimer stability; distal transmit changes to active site. These insights will inform continuing antiviral targeting...

The escape mutant of HIV-1 protease (PR) containing 20 mutations (PR20) undergoes efficient polyprotein processing even in the presence clinical inhibitors (PIs). PR20 shows >3 orders magnitude decreased affinity for PIs darunavir (DRV) and saquinavir (SQV) relative to PR. Crystal structures crystallized with yttrium, substrate analogue p2-NC, DRV, SQV reveal three distinct conformations flexible flaps diminished interactions through combination multiple mutations. yttrium at active site...

Design, synthesis, and evaluation of a new class exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity drug-resistance profiles. In fact, this inhibitor showed several orders magnitude improved over the FDA approved drug darunavir. This incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as P2 ligand aminobenzothiazole P2' with (R)-hydroxyethylsulfonamide isostere. The for has been synthesized efficiently in...

We report structural analysis of HIV protease variant PRS17 which was rationally selected by machine learning to represent wide classes highly drug-resistant variants. Crystal structures were solved in the inhibitor-free form and complex with antiviral inhibitor, darunavir. Despite its 17 mutations, has only one mutation (V82S) inhibitor/substrate binding cavity, yet exhibits high resistance all clinical inhibitors. none major mutations (I47V, I50V, I54ML, L76V I84V) associated darunavir...

Herein we report the design, synthesis, X-ray structural, and biological studies of an exceptionally potent HIV-1 protease inhibitor, compound 5 ((3S,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl ((2S,3R)-4-((2-(cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)carbamate). Using structure-based incorporated unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran as P2-ligand, a cyclopropylaminobenzothiazole P2'-ligand,...

A healthier HAART: We report the design, synthesis, biological evaluation, and X-ray crystallographic analysis of a new class HIV-1 protease inhibitors. Compound 4 proved to be an extremely potent inhibitor toward various multidrug-resistant variants, representing near 10-fold improvement over darunavir (DRV). also blocked dimerization with at least greater potency than DRV. Detailed facts importance specialist readers are published as "Supporting Information". Such documents peer-reviewed,...

The design, synthesis, and biological evaluation of a series HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in active site. Inhibitors 16a 16f showed excellent enzyme inhibitory antiviral activity, although incorporation sulfone functionality resulted decrease potency. Both maintained activity against panel multidrug resistant variants. A...

Nitronate monooxygenase (NMO) oxidizes the mitochondrial toxin propionate 3-nitronate (P3N) to malonate semialdehyde. The enzyme has been previously characterized biochemically in fungi, but no structural information is available. Based on amino acid similarity 4,985 genes are annotated GenBankTM as NMO. Of these, 4,424 (i.e. 89%) bacterial genes, including several Pseudomonads that have shown use P3N growth substrate. Here, we cloned and expressed gene pa4202 of Pseudomonas aeruginosa PAO1,...

The design, synthesis, and biological evaluation of a new class HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands variety sulfonamide derivatives P2′ are described. A number ring sizes various substituent effects were investigated to enhance ligand–backbone interactions in active site. Inhibitors 5c 5d this unprecedented 6–5–5 system ligand, an aminobenzothiazole difluorophenylmethyl P1 ligand exhibited exceptional enzyme inhibitory...

Many protein substrates of caspases are cleaved at noncanonical sites in comparison to the recognition motifs reported for three caspase subgroups. To provide insight into specificity and aid design drugs control cell death, crystal structures caspase‐7 were determined complexes with six peptide analogs (Ac‐DMQD‐Cho, Ac‐DQMD‐Cho, Ac‐DNLD‐Cho, Ac‐IEPD‐Cho, Ac‐ESMD‐Cho, Ac‐WEHD‐Cho) that span major The show S2 pocket can accommodate diverse residues. Glu is not required P3 position because...

The oxidation of reduced flavin cofactors by oxygen is a very important reaction that central to the chemical versatility hundreds flavoproteins classified as monooxygenases and oxidases. These enzymes are characterized bimolecular rate constants >or=10(5) M(-1) s(-1) produce water hydrogen peroxide, respectively. A hydrophobic cavity close reactive C(4a) atom has been previously identified in 3D structure but not flavoprotein In present study, we have investigated X-ray crystallography,...

Extreme drug resistant mutant of HIV-1 protease (PR) bearing 20 mutations (PR20) has been studied with the clinical inhibitor amprenavir (1) and two potent antiviral investigational inhibitors GRL-02031 (2) GRL-0519 (3). Clinical are >1000-fold less active on PR20 than wild-type enzyme, which is consistent dissociation constants (KL) from isothermal titration calorimetry 40 nM for 3, 178 amprenavir, 960 2. High resolution crystal structures PR20–inhibitor complexes revealed altered...

The HIV-1 protease (PR) mediates its own release (autoprocessing) from the polyprotein precursor, Gag-Pol, flanked by transframe region (TFR) and reverse transcriptase at N- C-termini, respectively. Autoprocessing N-terminus of PR stable dimer formation essential for catalytic activity, leading to infectious virus. An antiparallel β-sheet interface formed four C-terminal residues each subunit is important stability. Here, we present first high-resolution crystal structures model...

We describe here design, synthesis, and biological evaluation of a series highly potent HIV-1 protease inhibitors containing stereochemically defined unprecedented tricyclic furanofuran derivatives as P2 ligands in combination with variety sulfonamide P2′ ligands. These were designed to enhance the ligand-backbone binding van der Waals interactions active site. A number new ligand, an aminobenzothiazole ligand difluorophenylmethyl P1 displayed very enzyme inhibitory potency also showed...

We report the design, synthesis, biological evaluation, and X-ray crystal structure of a novel inhibitor bound to HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed interact with flap Gly48 carbonyl or amide NH in S2-subsite investigated potential those functionalized ligands combination hydroxyethylsulfonamide isosteres. Inhibitor 26 containing 3-(R)-hydroxyl group on Cp-THF core displayed most potent enzyme inhibitory antiviral activity. Our...

We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance ligand-binding site interactions the active site. In this context, we have carried out convenient syntheses of optically bis-THF and C4-substituted ligands using a [2,3]-sigmatropic rearrangement as key step. The synthesis provided access number derivatives. Incorporation these led series potent inhibitors. Inhibitor 23c turned be most (K(i) = 2.9 pM; IC(50) 2.4 nM) among An X-ray structure 23c-bound...

GRL-0519 (1) is a potent antiviral inhibitor of HIV-1 protease (PR) possessing tris-tetrahydrofuran (tris-THF) at P2. The high resolution X-ray crystal structures 1 in complexes with single substitution mutants PRR8Q, PRD30N, PRI50V, PRI54M, and PRV82A were analyzed relation to kinetic data. smaller valine side chain PRI50V eliminated hydrophobic interactions the other subunit consistent 60-fold worse inhibition. Asn30 PRD30N showed altered neighboring residues 18-fold Mutations V82A I54M...

We have designed, synthesized, and evaluated a new class of potent HIV-1 protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. developed an enantioselective synthesis these oxazolidinones utilizing key o-iodoxybenzoic acid mediated cyclization. Several displayed good to excellent activity toward significant antiviral in MT-4 cells. Compound 4k has shown enzyme Ki 40 pM IC50 31 nM. Inhibitors 4l were against panel highly resistant multidrug-resistant variants,...

We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series HIV-1 protease inhibitors. designed variety functionalized biphenyl derivatives to make enhanced van der Waals interactions in S1 subsite protease. These were conveniently synthesized using Suzuki–Miyaura cross-coupling reaction as key step. examined potential these biphenyl-derived P1 ligands combination with 3-(S)-tetrahydrofuranyl urethane bis-tetrahydrofuranyl P2 ligands. Inhibitor 21e,...