Last update 19 Sep 2024

DAP

Last update 19 Sep 2024

Basic Info

Synonyms

DAP, DAP-1, DAP1

+ [2]

Introduction

Ribosome-binding protein involved in ribosome hibernation, a process during which ribosomes are stabilized in an inactive state and preserved from proteasomal degradation (By similarity). Acts via its association with eiF5a (EIF5A and EIF5A2) at the polypeptide exit tunnel of the ribosome, preventing mRNA translation (By similarity). Involved in ribosome hibernation in the mature oocyte by preventing mRNA translation, leading to ribosome inactivation (By similarity). Ribosomes, which are produced in large quantities during oogenesis, are stored and translationally repressed in the oocyte and early embryo (By similarity). Also acts as a negative regulator of autophagy (PubMed:20537536). Involved in mediating interferon-gamma-induced cell death (PubMed:7828849).

Drugs associated with DAP

HG-1026

Target

DAP x EIF4G2 x HPRT1

Mechanism

DAP gene modulators [+2]

Active Org.-

Originator Org.

Human Genome Sciences, Inc.

Active Indication-

Inactive Indication-

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with DAP

100 Translational Medicine associated with DAP

0 Patents (Medical) associated with DAP

684

Literatures (Medical) associated with DAP

13 Jun 2024·ACS Medicinal Chemistry Letters

Potent, Selective, and Orally Bioavailable Quinazoline-Based STK17A/B Dual Inhibitors

Article

Author: Shah, Ashish ; Schurer, Stephan C. ; Chaudhry, Sana ; Zhang, Ziming ; Castro, Jesus R. ; Feng, Yangbo ; Afaghani, Jumana ; Taylor, Justin ; Khurshid, Rabia ; Nicholls, Miah ; Totiger, Tulasigeri M.

STK17A is a novel uncharacterized member of the death-associated protein family of serine and threonine kinases.Overexpression of STK17A is observed in many cancers.We identified a lead compound that is based on a quinazoline core.Optimizations of the lead compound led to the discovery of potent and selective STK17A/B inhibitors with drug-like properties and oral bioavailability.Compound 9 had an STK17A inhibitory IC50 of 23 nM.Based on profiling studies against two wild-type kinase panels (375 and 398 kinases, resp.), compound 9 had strong inhibition of both STK17A and STK17B but moderate off-target inhibition only for AAK1, MYLK4, and NEK3/5.In addition, compound 9 had good oral bioavailability, paving the way for in vivo studies against various cancers.

09 May 2024·The Journal of Physical Chemistry B

Elucidating Daptomycin’s Antibacterial Efficacy: Insights into the Tripartite Complex with Lipid II and Phospholipids in Bacterial Septum Membrane

Article

Author: Patra, Niladri ; Srivastava, Diship

This study elucidated the mechanism of formation of a tripartite complex containing daptomycin (Dap), lipid II, and phospholipid phosphatidylglycerol in the bacterial septum membrane, which was previously reported as the cause of the antibacterial action of Dap against gram-positive bacteria via molecular dynamics and enhanced sampling methods. Others have suggested that this transient complex ushers in the inhibition of cell wall synthesis by obstructing the downstream polymerization and cross-linking processes involving lipid II, which is absent in the presence of cardiolipin lipid in the membrane. In this work, we observed that the complex was stabilized by Ca²⁺-mediated electrostatic interactions between Dap and lipid head groups, hydrophobic interaction, hydrogen bonds, and salt bridges between the lipopeptide and lipids and was associated with Dap concentration-dependent membrane depolarization, thinning of the bilayer, and increased lipid tail disorder. Residues Orn6 and Kyn13, along with the DXDG motif, made simultaneous contact with constituent lipids, hence playing a crucial role in the formation of the complex. Incorporating cardiolipin into the membrane model led to its competitively displacing lipid II away from the Dap, reducing the lifetime of the complex and the nonexistence of lipid tail disorder and membrane depolarization. No evidence of water permeation inside the membrane hydrophobic interior was noted in all of the systems studied. Additionally, it was shown that using hydrophobic contacts between Dap and lipids as collective variables for enhanced sampling gave rise to a free energy barrier for the translocation of the lipopeptide. A better understanding of Dap's antibacterial mechanism, as studied through this work, will help develop lipopeptide-based antibiotics for rising Dap-resistant bacteria.

06 Mar 2024·Antimicrobial Agents and Chemotherapy

LiaX is a surrogate marker for cell envelope stress and daptomycin non-susceptibility in Enterococcus faecium

Article

Author: Shamoo, Yousif ; Khan, Ayesha ; Simar, Shelby R ; Hanson, Blake M ; Panesso, Diana ; Zervos, Marcus ; Atterstrom, Rachel ; Valdez, Lizbet ; Rincon, Sandra ; Nguyen, April H ; Shelburne, Samuel A ; Rydell, Kirsten ; Jones, Mary N ; Hood, Kara S ; DeTranaltes, Andrea M ; Sahasrabhojane, Pranoti V ; Pemberton, Orville A ; Axell-House, Dierdre B ; Miller, William R ; Reyes, Jinnethe ; Tran, Truc T ; Arias, Cesar A ; Singh, Kavindra V ; Suleyman, Geehan

ABSTRACT Daptomycin (DAP) is often used as a first-line therapy to treat vancomycin-resistant Enterococcus faecium infections, but emergence of DAP non-susceptibility threatens the effectiveness of this antibiotic. Moreover, current methods to determine DAP minimum inhibitory concentrations (MICs) have poor reproducibility and accuracy. In enterococci, DAP resistance is mediated by the LiaFSR cell membrane stress response system, and deletion of liaR encoding the response regulator results in hypersusceptibility to DAP and antimicrobial peptides. The main genes regulated by LiaR are a cluster of three genes, designated liaXYZ . In Enterococcus faecalis , LiaX is surface-exposed with a C-terminus that functions as a negative regulator of cell membrane remodeling and an N-terminal domain that is released to the extracellular medium where it binds DAP. Thus, in E. faecalis , LiaX functions as a sentinel molecule recognizing DAP and controlling the cell membrane response, but less is known about LiaX in E. faecium . Here, we found that liaX is essential in E. faecium with an activated LiaFSR system. Unlike E. faecalis , E. faecium LiaX is not detected in the extracellular milieu and does not appear to alter phospholipid architecture. We further postulated that LiaX could be used as a surrogate marker for cell envelope activation and non-susceptibility to DAP. For this purpose, we developed and optimized a LiaX enzyme-linked immunosorbent assay (ELISA). We then assessed 86 clinical E. faecium bloodstream isolates for DAP MICs and used whole genome sequencing to assess for substitutions in LiaX. All DAP-resistant clinical strains of E. faecium exhibited elevated LiaX levels. Strikingly, 73% of DAP-susceptible isolates by standard MIC determination also had elevated LiaX ELISAs compared to a well-characterized DAP-susceptible strain. Phylogenetic analyses of predicted amino acid substitutions showed 12 different variants of LiaX without a specific association with DAP MIC or LiaX ELISA values. Our findings also suggest that many E. faecium isolates that test DAP susceptible by standard MIC determination are likely to have an activated cell stress response that may predispose to DAP failure. As LiaX appears to be essential for the cell envelope response to DAP, its detection could prove useful to improve the accuracy of susceptibility testing by anticipating therapeutic failure.

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