- |||||||||| SQ-109 / Sequella
Review, Journal: Recent advances in mycobacterial membrane protein Large 3 inhibitor drug design for mycobacterial infections. (Pubmed Central) - Jun 16, 2023
The hydrophobic character of most MmpL3 series identified to date seem to drive antimycobacterial potency resulting in poor bioavailability, which is a significant impediment to their development. There is also a need for more high-throughput and informative assays to elucidate the precise mechanism of action of MmpL3 inhibitors and drive the rational optimization of analogues.
- |||||||||| SQ-109 / Sequella
Journal: Study of SQ109 analogs binding to mycobacterium MmpL3 transporter using MD simulations and alchemical relative binding free energy calculations. (Pubmed Central) - May 2, 2023
The binding assays in micelles suggested that the binding affinity of the SQ109 analogs was increased for the larger, more hydrophobic adducts, which was consistent with our results from MD simulations of the SQ109 analogues suggesting that sizeable C-2 adamantyl adducts of SQ109 can fill a lipophilic region between Y257, Y646, F260 and F649 in MmpL3. This was confirmed quantitatively by our calculations of the relative binding free energies using the thermodynamic integration coupled with MD simulations method with a mean assigned error of 0.74
- |||||||||| SQ-109 / Sequella
Journal: Pharmacophore based virtual screening & molecular docking approach for identification of mycobacterial membrane protein large 3 (MmpL3) inhibitors. (Pubmed Central) - Dec 27, 2022
Based on a set of 220 compounds showing anti-tubercular activity proposed to target MmpL3 transporter with MIC values ranging from 0.003 to 737 μM, a 5-point pharmacophore ADHHR_2 model possessing one hydrogen acceptor, one hydrogen donor, two hydrophobic groups and an aromatic ring system was generated. The model validated by enrichment study was used to screen Asinex and DrugBank database to identify a potential lead compound such as DrugBank_6059 that was found to show better binding affinity (-11.36) and hydrophobic interactions with target protein in comparison to standard drug SQ109.Communicated by Ramaswamy H. Sarma.
- |||||||||| SQ-109 / Sequella
Review, Journal: MmpL3 Inhibition as a Promising Approach to Develop Novel Therapies against Tuberculosis: A Spotlight on SQ109, Clinical Studies, and Patents Literature. (Pubmed Central) - Nov 16, 2022
SQ109 has demonstrated activity against drug-sensitive (DS) and drug-resistant (DR) Mycobacterium tuberculosis (Mtb) and a synergistic effect with isoniazid (INH), rifampicin (RIF), clofazimine (CFZ), and bedaquiline (BNQ)...The combinations of SQ109 with other anti-TB drugs (chloroquine, hydroxychloroquine, and sutezolid) have also been claimed in the patent literature...Developing MmpL3 inhibitors is a promising approach to fighting the challenges associated with DS-TB and DR-TB. The authors foresee MmpL3 inhibitors such as SQ109 as future drugs for TB treatment.
- |||||||||| telacebec (Q203) / Qurient, macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Synergistic Effect of Q203 Combined with PBTZ169 against Mycobacterium tuberculosis. (Pubmed Central) - Nov 3, 2022
Zebrafish (Danio rerio)-Mycobacterium marinum infection and a curing model further validated the synergistic effect of Q203 and PBTZ169 in vivo. In this study, the synergy between these two new antituberculosis drugs, Q203 and PBTZ169, is an important finding that could lead to the development of a new TB regimen.
- |||||||||| Acomplia (rimonabant) / Sanofi, SQ-109 / Sequella
Journal: Molecular Modelling and Atomistic Insights into the Binding Mechanism of MmpL3 Mtb. (Pubmed Central) - Sep 20, 2022
Protein-ligand interactions were analysed using molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann surface area computations. Novel residues Gln32, Leu165, Ile414, and Phe35 were identified as critical for binding to M. tuberculosis MmpL3, and conformational dynamics upon inhibitor binding were discussed.
- |||||||||| SQ-109 / Sequella
Journal: Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation. (Pubmed Central) - May 27, 2022
In addition, selected derivatives showed promising cytotoxicity profiles against human pulmonary fibroblasts and/or murine macrophages, proved to be effective in inhibiting the growth of intracellular mycobacteria, and elicited either bactericidal effects, or bacteriostatic activity comparable to 1. Computational studies revealed that the new compounds bind to the putative target, MmpL3, in a manner similar to that of known inhibitors BM212 and SQ109.
- |||||||||| SQ-109 / Sequella
Journal: Computational design of MmpL3 inhibitors for tuberculosis therapy. (Pubmed Central) - Apr 29, 2022
For the study, we have selected SQ109 derivatives as Mmpl3 inhibitor, which holds non-covalent property...Molecular dynamics simulations integrated with MM-PBSA free energy calculations identified that MmpL3-ZINC000000016638 complex was more stable. Study can be further extended for synthesis and biological evaluation, derivatization of active compound to identify potential and safe lead compounds for effective tuberculosis therapy.
- |||||||||| SQ-109 / Sequella
Journal: MMPL-Family Proteins in Bacteria, Protozoa, Fungi, Plants and Animals: A Bioinformatics and Structural Investigation. (Pubmed Central) - Mar 17, 2022
The animal, fungal, apicomplexan and plant proteins have larger extra-membrane domains than are found in the bacterial MmpL3, but they have a similar TM domain architecture, with the introduction of a (catalytically essential) Phe>His residue change, and a Ser/Thr H-bond network, involved in H -transport. Overall, the results are of interest since they show that MMPL-family proteins are present in essentially all life-forms: archaea, bacteria, protozoa, fungi, plants and animals and, where known, they are involved in "lipid" (glycolipid, phospholipid, sphingolipid, fatty acid, cholesterol, ergosterol) transport, powered by transmembrane molecular pumps having similar structures.
- |||||||||| SQ-109 / Sequella
Journal: Specifically targeting Mtb cell-wall and TMM transporter: the development of MmpL3 inhibitors. (Pubmed Central) - Feb 4, 2022
A series of inhibitors (such as SQ109, AU1235, BM212, etc.) through experimental screening have been reported in succession, especially SQ109 has entered the clinical stage. In this paper, the structural biology information of target MmpL3 was summarized, and the structure-activity relationship (SAR) of inhibitors reported in recent years and their inhibitory mechanism both were reviewed, aiming to provide help for the rational design of MmpL3 inhibitors in the future.
- |||||||||| SQ-109 / Sequella
Preclinical, Journal: Structure, In Vivo Detection, and Antibacterial Activity of Metabolites of SQ109, an Anti-Infective Drug Candidate. (Pubmed Central) - Sep 11, 2021
In the rabbit TB model, it is thus the gradual accumulation of nonmetabolized SQ109 in tissues to therapeutic levels that leads to good efficacy. Our results also provide new insights into how SQ109 binds to its target MmpL3, based on our mass spectroscopy results which indicate that the charge in SQ109 is primarily localized on the geranyl nitrogen, explaining the very short distance to a key Asp found in the X-ray structure of SQ109 bound to MmpL3.
- |||||||||| SQ-109 / Sequella
PK/PD data, Preclinical, Journal: Pharmacokinetics and target attainment of SQ109 in plasma and human-like tuberculosis lesions in rabbits. (Pubmed Central) - Aug 26, 2021
SQ109 exhibits extremely low frequency of resistance, unprecedented among all TB drugs so far. Here we characterize the pharmacokinetics and activity of SQ109 at the site of TB disease to inform the selection of drug regimens that account for its lesion-centric pharmacokinetic-pharmacodynamic parameters and best leverage its contribution to efficient disease cure.
- |||||||||| Lamprene (clofazimine) / Novartis
Review, Journal: An overview of new antitubercular drugs, drug candidates, and their targets. (Pubmed Central) - Jul 9, 2021
The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid...These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug-target interactions, and their structure-activity relationship.
- |||||||||| Multaq (dronedarone) / Sanofi, SQ-109 / Sequella
Review, Journal: Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi. (Pubmed Central) - Jun 22, 2021
Miltefosine similarly induces a large increase in the [Ca] acting on the sphingosine-activated Ca channel, the mitochondrion and acidocalcisomes. These examples, in conjunction with other evidence we review herein, strongly support targeting Ca homeostasis as a strategy against Chagas disease.
- |||||||||| rifampicin / Generic mfg.
Journal: NanoLuciferase reporter mycobacteriophage for sensitive and rapid detection of Mycobacterium tuberculosis drug susceptibility. (Pubmed Central) - Apr 10, 2021
Leveraging the tractability of the TM4 mycobacteriophage and the sensitivity of the NanoLuciferase reporter enzyme, the present work describes an evolution of phage-mediated detection and drug susceptibility testing of M. tuberculosis, adding a valuable tool in drug discovery and basic biology research. With additional validation, this system may play a role as a quantitative phenotypic reference method and complement to genotypic methods for diagnosis and antibiotic susceptibility testing.
- |||||||||| SQ-109 / Sequella
Journal: Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450. (Pubmed Central) - Feb 26, 2021
The hydroxylated SQ109 presumably forms stabilizing H-bonds with its target, Mycobacterial membrane protein Large 3 (MmpL3). We anticipate that Mtb CYPs could function as analogs of drug-metabolizing human CYPs affecting pharmacokinetics and pharmacodynamics of antitubercular (anti-TB) drugs.
- |||||||||| SQ-109 / Sequella
Journal: Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO. (Pubmed Central) - Jan 26, 2021
These include the drug candidate SQ109, which has progressed to phase IIb/III clinical trials...Structural analysis of the two structures reveals that these inhibitors target the proton relay pathway to block the activity of MmpL3. The findings presented here enrich our understanding of the binding modes of MmpL3 inhibitors and provide directions to enable further rational drug design targeting MmpL3.
- |||||||||| SQ-109 / Sequella
Journal: 1H-benzo[d]imidazole derivatives affect MmpL3 in Mycobacterium tuberculosis. (Pubmed Central) - Aug 4, 2020
Metabolic labeling and quantitative TLC analysis of radiolabeled lipids from M. tuberculosis cultures treated with the benzoimidazoles indicated an inhibition of trehalose dimycolate (TDM) synthesis, as well as reduced levels of mycolylated arabinogalactan, in agreement with the inhibition of MmpL3 activity. Overall, this study emphasizes the pronounced activity of 1H-benzo[d]imidazole derivatives in interfering with mycolic acid metabolism and their potential for therapeutic application in the fight against tuberculosis.
- |||||||||| Acomplia (rimonabant) / Sanofi, SQ-109 / Sequella
Journal: Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target. (Pubmed Central) - Nov 29, 2019
SQ109, AU1235, ICA38, and rimonabant bind inside the transmembrane region and disrupt these Asp-Tyr pairs. This structural data will greatly advance the development of MmpL3 inhibitors as new TB drugs.
- |||||||||| SQ-109 / Sequella
Journal: HC2091 kills Mycobacterium tuberculosis by targeting the MmpL3 mycolic acid transporter. (Pubmed Central) - Sep 4, 2019
RNA-seq transcriptional profiling and lipid profiling of Mtb treated with HC2091 or SQ109 show that both compounds target a similar pathway. HC2091 has a dissimilar chemical structure from previously described MmpL3 inhibitors, supporting that HC2091 is a new class of MmpL3 inhibitor.
- |||||||||| SQ-109 / Sequella
Enrollment change, Trial withdrawal: Evaluation of SQ109 Plus PPI in Urea Breath Test-Positive Volunteers (clinicaltrials.gov) - Nov 17, 2015
P2a, N=0, Withdrawn,
PRS Regimen III, with three nonstandard drugs, can potentially treat both drug-sensitive and most drug-resistant tuberculosis. N=30 --> 0 | Suspended --> Withdrawn
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