Successful surgeries involving orthopedic implants depend on the avoidance of biofilm development on the implant surface during the early postoperative period. Here, we investigate the potential of novel antibacterial compounds-second-generation lipophosphonoxins (LPPOs II)-as additives to surgical bone cements. We demonstrate (i) excellent thermostability of LPPOs II, which is essential to withstand elevated temperatures during exothermic cement polymerization; (ii) unchanged tensile strength and elongation at the break properties of the composite cements containing LPPOs II compared to cements without additives; (iii) convenient elution kinetics on the order of days; and (iv) the strong antibiofilm activity of the LPPO II-loaded cements even against bacteria resistant to the medicinally utilized antibiotic, gentamicin. Thus, LPPOs II display promising potential as antimicrobial additives to surgical bone cements.
- Klíčová slova
- lipofosfonoxiny,
- MeSH
- antiinfekční látky * analýza terapeutické užití MeSH
- biofilmy MeSH
- grampozitivní bakterie MeSH
- hydrofobní a hydrofilní interakce MeSH
- iminosacharidy analýza terapeutické užití MeSH
- infekce spojené s protézou prevence a kontrola MeSH
- kostní cementy * analýza terapeutické užití MeSH
- lidé MeSH
- mikrobiální testy citlivosti metody MeSH
- nukleosidy analýza terapeutické užití MeSH
- organofosfonáty analýza terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- práce podpořená grantem MeSH
HIV integrase (IN) catalyzes the insertion of proviral DNA into the host cell chromosome. While IN has strict sequence requirements for the viral cDNA ends, the integration site preference has been shown to be very diverse. Here, we mapped the HIV IN strand transfer reaction requirements using various short oligonucleotides (ON) that mimic the target DNA. Most double stranded DNA dodecamers served as excellent IN targets with variable integration efficiency depending mostly on the ON sequences. The preferred integration was lost with any changes in the geometry of the DNA double helical structures. Various hairpin-loop-forming ONs also served as efficient integration targets. Similar integration preferences were also observed for ONs, in which the nucleotide hairpin loop was replaced with a flexible aliphatic linker. The integration biases with all target DNA structures tested were significantly influenced by changes in the resulting secondary ON structures.
- MeSH
- dimerizace MeSH
- DNA virů genetika MeSH
- HIV-1 genetika MeSH
- HIV-integrasa genetika izolace a purifikace MeSH
- integrace viru genetika MeSH
- katalýza MeSH
- konformace nukleové kyseliny MeSH
- molekulární sekvence - údaje MeSH
- oligonukleotidy genetika MeSH
- sekvence nukleotidů MeSH
- substrátová specifita genetika MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- práce podpořená grantem MeSH
Retroviral integrase participates in two catalytic reactions, which require interactions with the two ends of the viral DNA in the 3'processing reaction, and with a targeted host DNA in the strand transfer reaction. The 3'-hydroxyl group of 2'-deoxyadenosine resulting from the specific removing of GT dinucleotide from the viral DNA in the processing reaction provides the attachment site for the host DNA in a transesterification reaction. We synthesized oligonucleotides (ONs) of various lengths that mimic the processed HIV-1 U5 terminus of the proviral long terminal repeat (LTR) and are ended by 2'-deoxyadenosine containing a 3'-O-phosphonomethyl group. The duplex stability of phosphonomethyl ONs was increased by covalent linkage of the modified strand with its complementary strand by a triethylene glycol loop (TEG). Modified ONs containing up to 10 bases inhibited in vitro the strand transfer reaction catalyzed by HIV-1 integrase at nanomolar concentrations.
- MeSH
- financování organizované MeSH
- HIV - dlouhá koncová repetice genetika MeSH
- HIV-integrasa účinky léků MeSH
- inhibitory HIV-integrasy farmakologie chemická syntéza MeSH
- konformace nukleové kyseliny MeSH
- kyseliny fosforu MeSH
- molekulární mimikry MeSH
- oligonukleotidy farmakologie chemická syntéza MeSH
A number of structurally diverse nucleoside phosphonic acids have been tested against human recombinant thymidine phosphorylase and human platelets supernatant using 2'-deoxy-5-nitrouridine as the substrate. We have selected several inhibitors working at micromolar level as lead structures for further evaluation.
- MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- inhibitory enzymů chemie farmakologie MeSH
- křečci praví MeSH
- kyseliny fosforité chemie MeSH
- lidé MeSH
- nukleosidy chemie farmakologie MeSH
- thymidinfosforylasa antagonisté a inhibitory chemie MeSH
- trombocyty enzymologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A novel series of racemic piperidin-3-yl and piperidin-4-yl derivatives of nucleobases and their phosphonate derivatives were prepared.
Synthesis of a novel cyanoethyl-type linker suitable for the solid-phase synthesis of oligodeoxynucleotides possessing terminal 3'-phosphate group is described. Since the linker is a 2-substituted 2-cyanoethanol, the release of the synthesized oligonucleotide from the solid support is accomplished by ß-elimination in the ammonia deprotection step.
