Design and synthesis of HIV-1 protease inhibitors for a long-acting injectable drug application

Kesteleyn, Bart; Amssoms, Katie; Schepens, Wim; Haché, Geerwin; Verschueren, Wim; Vreken, Wim Van de; Rombauts, Klara; Meurs, Greet; Sterkens, Patrick; Stoops, Bart; Baert, Lieven; Austin, Nigel; Wegner, Jörg K.; Masungi, Chantal; Dierynck, Inge; Lundgren, Stina; Jönsson, Daniel; Parkes, K. E. B.; Kalayanov, G. D.; Wallberg, Hans; Rosenquist, Åsa; Samuelsson, Bertil; Emelen, Kristof Van; Thuring, Jan Willem

doi:10.1016/j.bmcl.2012.10.095

“…In these early studies, there was little to distinguish poloxamer 338 from D-alpha-tocopheryl polyethylene glycol 1000 succinate (Vit-E TPGS) as surfactants. However, other preclinical experiments have shown that the choice of surfactant can be influential [17]. Some significant challenges emerged from this preclinical research:…”

Section: Key Pointsmentioning

confidence: 99%

Formulation and pharmacology of long-acting rilpivirine

Williams

¹

,

Crauwels²,

Basstanie³

2015

Current Opinion in HIV and AIDS

View full text Add to dashboard Cite

show abstract

“…Efforts to improve potency, pharmacokinetics, and resistance profiles of HIV-1 PIs have led to the discovery of exceptionally potent compounds exhibiting a wide range of properties. 5,[10][11][12][13][14] In recent years, these efforts have focused mainly on exploring DRV analogues with similar sulfonamide-based dipeptide isosteres and P2/P2 moieties. Many analogues of DRV with modifications at P1/P1…”

Section: Introductionmentioning

confidence: 99%

“…Efforts to improve potency, pharmacokinetics, and resistance profiles of HIV-1 PIs have led to the discovery of exceptionally potent compounds exhibiting a wide range of properties. ,− In recent years, these efforts have focused mainly on exploring DRV analogues with similar sulfonamide-based dipeptide isosteres and P2/P2′ moieties. Many analogues of DRV with modifications at the P1/P1′ and P2/P2′ positions have been explored extensively, ,− including novel bis-THF analogues showing improved hydrogen bonding and vdW interactions with the protease. − Moreover, detailed structural analyses informing structure-based design of inhibitors with the DRV scaffold have been reported numerous times including recent structures determined by neutron crystallography. ,,,− …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere

Rusere

¹

,

Lockbaum

²

,

Henes

³

et al. 2020

View full text Add to dashboard Cite

The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C 2-symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2 position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2 position without significantly affecting potency. However, the group on the opposite P2/P2 position had a dramatic effect on potency depending on the size and shape of the side chain. Cocrystal structures of inhibitors with wild-type HIV-1 protease revealed that the bis-THF moiety retained similar interactions as observed in the darunavir-protease complex regardless of position on the Phe-Phe isostere. Analyses of cocrystal structures and molecular dynamics simulations provide insights for optimizing HIV-1 PIs containing bis-THF in non-sulfonamide dipeptide isosteres.

show abstract

“…10–12 Following AC determination at a given synthesis step, there is usually a need to maximize enantiomeric excess (EE) where the accurate measurement of EE is critical. 7,13–15 Considering the plausible, widespread implementation of VCD spectroscopy to real-time, kinetic monitoring of EE, 16,17 the rapid automated removal of baselines prior to calibration is a pressing concern. 18…”

Section: Introductionmentioning

confidence: 99%

Automatic Baseline Correction of Vibrational Circular Dichroism Spectra

Weakley

¹

,

Aston

²

,

Griffiths

³

2013

View full text Add to dashboard Cite

A three-phase, computational method for the baseline correction of vibrational circular dichroism (VCD) spectra has been proposed. In the first phase the raw spectrum is subdivided into m segments (or regions) resulting in p rough estimates of the baseline. A second phase uses gradient characteristics to discriminate between baseline and band response for each baseline, in turn. In the final phase all baselines are interrogated simultaneously by assigning the median estimate of each differential response’s distribution to the true baseline. Using VCD spectra of (R)-camphor as test cases, this work demonstrated that the accurate removal of baseline components is readily achievable with minimal user intervention. Baseline correction also demonstrated flexibility in that prior information, such as the symmetry of a baselinefree VCD spectrum, is readily used during the correction protocol. Although three adjustable parameters are present in the base algorithm, optimal performance and full automation were attainable following the use of analysis of variance (ANOVA) to analyze simulated bipolar spectra. These ANOVAs suggested that band point discrimination could be discarded and the remaining two default parameters adopted.

show abstract

Design and synthesis of HIV-1 protease inhibitors for a long-acting injectable drug application

Cited by 10 publications

References 22 publications

Formulation and pharmacology of long-acting rilpivirine

Formulation and pharmacology of long-acting rilpivirine

Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere

Automatic Baseline Correction of Vibrational Circular Dichroism Spectra

Contact Info

Product

Resources

About