Abstract:
:Targeting protein-protein interactions, such as the HIV-1 gp120-CD4 interface, has become a cutting-edge approach in the current drug discovery scenario. Many small molecules have been developed so far as inhibitors of the interaction between CD4 and HIV-1 gp120. However, due to a variety of reasons such as solubility, drug toxicity and drug resistance, these inhibitors have failed to prove clinically useful. As such, the identification of novel compounds that bind to protein-protein interactions is still a research area of considerable interest. Here, a structure-based virtual screening approach was successfully applied with the aim of identifying novel HIV-1 entry inhibitors targeting the Phe43 pocket of HIV-1 gp120. Several compounds able to inhibit viral replication in cell culture were identified, with the best agent endowed with an EC(50) value of 0.9 μM. Inactivity of all the identified hits toward a mutant (Met475Ile) strain strongly suggests that they interact in the Phe43 cavity of gp120, as intended. Remarkably, all of these small molecules have a chemical scaffold unrelated to any known class of entry inhibitors reported thus far. Overall, our strategy led to the identification of four novel chemical scaffolds that inhibit HIV-1 replication through the destabilization of the HIV-1 gp120-CD4 interface.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Tintori C,Selvaraj M,Badia R,Clotet B,Esté JA,Botta Mdoi
10.1002/cmdc.201200584subject
Has Abstractpub_date
2013-03-01 00:00:00pages
475-83issue
3eissn
1860-7179issn
1860-7187journal_volume
8pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::Polo-like kinase 1 (PLK1) plays crucial functions in multiple stages of mitosis and is considered to be a potential drug target for cancer therapy. The functions of PLK1 are mediated by its N-terminal kinase domain and C-terminal polo-box domain (PBD). Most inhibitors targeting the kinase domain of PLK1 have a selecti...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402284
更新日期:2015-01-01 00:00:00
abstract::Disulfide bridges that stabilize the native conformation of conotoxins pose a challenge in the synthesis of smaller conotoxin analogues. Herein we describe the synthesis of a minimized analogue of the analgesic mu-conotoxin KIIIA that blocks two sodium channel subtypes, the neuronal Na(V)1.2 and skeletal muscle Na(V)1...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800292
更新日期:2009-03-01 00:00:00
abstract::A library of 40,000 compounds was screened for inhibitors of 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) protein from Arabidopsis thaliana using a photometric assay. A thiazolopyrimidine derivative resulting from the high-throughput screen was found to inhibit the IspF proteins of Mycobacterium tuberculosi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000083
更新日期:2010-07-05 00:00:00
abstract::The synthesis of SCF3 as well as SeCF3 isosteres of two OCF3 -containing drugs was achieved through visible light and copper-catalyzed processes. Herein, we show that chalcogen replacement modulates physicochemical and ADME properties without introducing intrinsic liabilities. The SCF3 and SeCF3 groups are more lipoph...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900452
更新日期:2019-09-04 00:00:00
abstract::In the present review the crucial role of the guanidinium functional group in facilitating the transport of dendritic polymers through liposomal and cell membranes is discussed, along with other structural features of guanidinylated dendritic polymers that fine-tune their transport properties, and even determine their...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.200800190
更新日期:2008-11-01 00:00:00
abstract::Even though immunotherapy has radically changed the search for anticancer therapies, there are still many different pathways that are open to intervention with traditional small molecules. To expand our investigation in the anticancer field, we report here a new series of compounds in which our previous pyrazole and i...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000122
更新日期:2020-06-04 00:00:00
abstract::Histone deacetylases (HDACs) are promising drug targets for a variety of therapeutic applications. Herein we describe the design, synthesis, biological evaluation in cellular models of cancer, and preliminary drug metabolism and pharmacokinetic studies (DMPK) of a series of secondary and tertiary N-substituted 7-amino...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700449
更新日期:2017-12-19 00:00:00
abstract::Efavirenz (EFV), an antiretroviral that interacts clinically with co-administered drugs via activation of the pregnane X receptor (PXR), is extensively metabolized by the cytochromes P450. We tested whether its primary metabolite, 8-hydroxyEFV (8-OHEFV) can activate PXR and potentially contribute to PXR-mediated drug-...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700730
更新日期:2018-04-06 00:00:00
abstract::Members of the Eph receptor tyrosine kinase family play essential roles in the pathogenesis of cancer and are therefore promising candidates for molecular imaging by positron emission tomography (PET), for example. In this regard, radiochemical access to novel PET radiotracers derived from potent inhibitors that targe...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200264
更新日期:2012-11-01 00:00:00
abstract::Quorum sensing has been implicated in the control of pathologically relevant bacterial behavior such as secretion of virulence factors, biofilm formation, sporulation, and swarming motility. The AI-2 quorum sensing pathway is found in both gram-positive and gram-negative bacteria. Therefore, antagonizing AI-2 quorum s...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800076
更新日期:2008-08-01 00:00:00
abstract::The natural product piperlonguminine (PL) has been shown to exert potential anticancer activity against several types of cancer via elevation of reactive oxidative species (ROS). However, the application of PL has been limited due to its poor water solubility and moderate activity. To improve PL's potency, we designed...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000660
更新日期:2020-10-21 00:00:00
abstract::Here we report the synthesis of a number of compounds structurally related to arginine methyltransferase inhibitor 1 (AMI-1). The structural alterations that we made included: 1) the substitution of the sulfonic groups with the bioisosteric carboxylic groups; 2) the replacement of the ureidic function with a bis-amidi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900459
更新日期:2010-03-01 00:00:00
abstract::Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes (T2DM). Ferulic acid is known for attenuating the insulin resistance and reducing the blood glucose in T2DM rats. In this work, we designed and synthesized a library of new ferulic acid amides (FAA), which could be considere...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000564
更新日期:2020-10-08 00:00:00
abstract::γ-Glutamylcyclotransferase (GGCT) depletion inhibits cancer cell proliferation. However, whether the enzymatic activity of GGCT is critical for the regulation of cancer cell growth remains unclear. In this study, a novel diester-type cell-permeable prodrug, pro-GA, was developed based on the structure of N-glutaryl-l-...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700660
更新日期:2018-01-22 00:00:00
abstract::A severe limitation in cancer therapy is the often insufficient differentiation between malign and benign tissue using known chemotherapeutics. One approach to decrease side effects is antibody-directed enzyme prodrug therapy (ADEPT). We have developed new glycosidic prodrugs such as (-)-(1S)-26 b based on the antibio...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800250
更新日期:2008-12-01 00:00:00
abstract::Monoamine oxidase B (MAO-B) is an important drug target for the treatment of neurological disorders. A series of 6-nitrobenzothiazole-derived semicarbazones were designed, synthesized, and evaluated as inhibitors of the rat brain MAO-B isoenzyme. Most of the compounds were found to be potent inhibitors of MAO-B, with ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200484
更新日期:2013-03-01 00:00:00
abstract::Cancer cells express high levels of CK2, and its inhibition leads to apoptosis. CK2 has therefore emerged as a new drug target for cancer therapy. A biligand inhibitor ARC-772 was constructed by conjugating 4-(2-amino-1,3-thiazol-5-yl)benzoic acid and a carboxylate-rich peptoid. ARC-772 was found to bind CK2 with a Kd...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700457
更新日期:2017-10-20 00:00:00
abstract::Serine- and metallo-β-lactamases present a threat to the clinical use of nearly all β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems. Efforts to develop metallo-β-lactamase (MBL) inhibitors require suitable screening platforms to allow the rapid determination of β-lactamase activity and eff...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300350
更新日期:2013-12-01 00:00:00
abstract::Because only a few studies have investigated the affinity and functional activity of NMDA receptor open channel blockers under the same assay conditions, a comparative study of common open channel blockers is of major interest. The pharmacological activities of MK-801, phencyclidine (PCP), dexoxadrol, etoxadrol, (S)- ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700810
更新日期:2018-03-06 00:00:00
abstract::TIBO- and TBO-like sulfone derivatives 1 and 2 were designed, synthesized, and tested for their ability to block the replication cycle of HIV-1 in infected cells. The anti-HIV-1 activities of sulfones 3, which were intermediates in the syntheses of 1 and 2, were also evaluated. Surprisingly, the sulfone analogues of T...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200500020
更新日期:2006-01-01 00:00:00
abstract::The histone methyltransferase SET7/9 methylates not only histone but also non-histone proteins as substrates, and therefore, SET7/9 inhibitors are considered candidates for the treatment of diseases. Previously, our group identified cyproheptadine, used clinically as a serotonin receptor antagonist and histamine recep...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800233
更新日期:2018-08-10 00:00:00
abstract::Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis belong to a group of infectious diseases known as neglected tropical diseases and are induced by infection with protozoan parasites named trypanosomatids. Drugs in current use have several limitations, and therefore new candidate drugs are required...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.201700259
更新日期:2017-08-22 00:00:00
abstract::Three photoswitchable tetrapeptides, based on a known synthetic antibacterial, were designed and synthesized to determine activity against Staphylococcus aureus. Each peptide contains an azobenzene photoswitch incorporated into either the N-terminal side chain (1), C-terminal side chain (2), or the C-terminus (3) to a...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000280
更新日期:2020-08-19 00:00:00
abstract::Plasmodium parasites kill 435 000 people around the world every year due to unavailable vaccines, a limited arsenal of antimalarial drugs, delayed treatment, and the reduced clinical effectiveness of current practices caused by drug resistance. Therefore, there is an urgent need to discover and develop new antiplasmod...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000653
更新日期:2020-11-24 00:00:00
abstract::A series of four stable synthetic bacteriochlorins was tested in vitro in HeLa cells for their potential in photodynamic therapy (PDT). The parent bacteriochlorin (BC), dicyano derivative (NC)(2)BC and corresponding zinc chelate (NC)(2)BC-Zn and palladium chelate (NC)(2)BC-Pd were studied. Direct dilution of a solutio...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200351
更新日期:2012-12-01 00:00:00
abstract::Selectivity is a central aspect of lead optimization in the drug discovery process. Medicinal chemists often try to decrease molecular flexibility to improve selectivity, given the common belief that the two are interdependent. To investigate the relationship between polypharmacology and conformational flexibility, we...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402389
更新日期:2015-02-01 00:00:00
abstract::Nitrogen mustards are an important class of bifunctional alkylating agents routinely used in chemotherapy. They react with DNA as electrophiles through the formation of highly reactive aziridinium ion intermediates. The antibiotic 593A, with potential antitumor activity, can be considered a naturally occurring piperid...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201400034
更新日期:2014-09-01 00:00:00
abstract::The polyether ionophore salinomycin (SAL) has captured much interest because of its potent activity against cancer cells and cancer stem cells. Our previous studies have indicated that C1/C20 double-modification of SAL is a useful strategy to generate diverse agents with promising biological activity profiles. Thus, h...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900593
更新日期:2020-01-17 00:00:00
abstract::Pharmaceutical companies are facing an increasing interest in new target identification and validation. In particular, extensive efforts are being made in the field of protein kinase inhibitors research and development, and the past ten years of effort in this field have altered our perception of the potential of kina...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.200600271
更新日期:2007-08-01 00:00:00
abstract::Two acyclic cucurbit[n]uril (CB[n])-type molecular containers that differ in the length of the (CH2 )n linker (M2C2: n=2, M2C4: n=4) between their aromatic sidewalls and sulfonate solubilizing groups were prepared and studied. The inherent solubilities of M2C2 (68 mm) and M2C4 (196 mm) are higher than the analogue wit...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600090
更新日期:2016-05-06 00:00:00