<p>Multidrug resistance is a major issue in treatment and eradication of diseases. There are many mechanisms by which pathogens develop multi drug resistance. Here we focus on the ability of pathogens to evade drug treatment by establishing multi drug resistant reservoirs. In the case of HIV, the virus is able to evade drug treatment and forms both latent and active replicating reservoirs throughout the body. In the case of many bacterial pathogens, multidrug resistance reservoirs are established within mammalian cells, such as macrophages. Many classes of antibiotics are unable to penetrate mammalian cells, making intracellular bacteria difficult to clear</p><p>Previously our research group has developed a Trojan horse strategy to deliver antivirals to HIV cellular reservoirs. Ester based prodrug dimers of abacavir, a reverse transcriptase inhibitor, acted to both inhibit efflux transporters at the BBB and revert to the monomeric therapy in the reducing environments of the cell. Herein we present a new group of sterically hindered carbonate based disulfide linkers that shows improved payload delivery of abacavir and maintain the stability of prodrug molecules towards hydrolysis. We employed these linker molecules to synthesize prodrug dimers of the HIV latency reversal agent prostratin with the hope of targeting latent HIV reservoirs. Payload release studies as well as latency reversal experiments with a latently infected T-helper cell model confirmed that the prostratin carbonate homodimers (<b>ProS₂Me₂</b> and <b>ProS₂Me₄</b>) were able to revert to monomeric prostratin and reverse HIV latency. We next sought to synthesize a prostrain-protease inhibitor heterodimer. While our initial study of a prostratin-lopinavir heterodimer employing this linker strategy (<b>ProLpvS₂Me₂</b>) did not show significant HIV latency reversal activity, we hope to expand our heterodimer studies to achieve dual therapeutic molecules that can both reverse HIV latency and deliver antivirals to HIV reservoirs.</p><p>In order to combat intracellular bacteria our group has focused on development of a novel class of cell penetrating peptides with intrinsic broad spectrum antimicrobial activity that are based on a repeating amino acid triad which forms a cationic amphiphilic polyproline helix (CAPH) scaffold. The first member of this class, <b>P14LRR</b>, exhibited clearance of intracellular bacteria and concentration dependent co-localization within mammalian cells. In efforts to optimize antimicrobial activity we have expanded the CAPHs library by adjusting the chain length between the proline backbone and the guanadinium groups of the cationic amino acids. The first peptide from this expanded library, <b>P14GAP</b> showed much greater cell penetration and antimicrobial activity against a wide range of pathogenic bacteria. However, <b>P14GAP</b> also showed greater toxicity towards mammalian cells, increased hemolysis, and greater membrane binding with mammalian cells as compared to <b>P14LRR</b>. Here we describe the design and synthesis of <b>P14GAP-C1</b>, which contains a methylene between the proline backbone and the guanadinium group. This new analogue decreased the hemolysis activity as compared to <b>P14GAP</b>, although similar membrane binding with mammalian cells was observed. This improvement in hemolysis activity and a slight improvement in cell viability may allow us to use higher concentrations of peptide to treat multidrug resistant bacterial infections.</p><p> </p>

Dans le but d’approfondir les connaissances fondamentales entre la structure des polymères associatifs intramoléculaires (polysavons) et leurs propriétés physico-chimiques en milieux aqueux, trois nouvelles familles de polymères amphiphiles cationiques ont été synthétisées par deux méthodes complémentaires permettant une grande variabilité de structure. Les polymères obtenus sont des poly(méth)acrylamides en peigne avec des groupes latéraux de type ammonium quaternaire portant une chaîne alkyle de taille variable. Une étude du comportement physico-chimique de ces polymères en solution, par viscosimétrie et spectroscopie de fluorescence avec deux sondes aux caractéristiques complémentaires, montre qu’ils présentent des propriétés de polysavons qui varient progressivement avec la structure des polymères amphiphiles étudiés, notamment la longueur de la chaîne alkyle latérale, la taille de l’espaceur entre les deux sites polaires amide et ammonium quaternaire et la masse molaire moyenne en nombre. En parallèle, la tensiométrie a montré que ces polyamphiphiles ont une très faible activité à l’interface eau/air confirmant la prédominance de l’effet hydrophobe, alors que les modèles moléculaires correspondants présentent d’excellentes propriétés tensio-actives. Des films de Langmuir ont ensuite été réalisés dans le cadre de la première étude de cette importance sur des polyamphiphiles cationiques. Dans ce domaine également, la grande variabilité de structure des polymères a permis des observations originales et de dégager de nouvelles relations entre la structure du polymère et les caractéristiques des isothermes de compression obtenues / In order to improve the fundamental knowledge of the relationships between the chemical structure of intramolecular associative polymers (polysoaps) and their physical chemical properties in aqueous media, three new families of cationic amphiphilic polymers were obtained by complementary methods offering great structure variability. The corresponding polymers were comb poly(meth)acrylamides with pendant ammonium groups with alkyl side chains of variable lengths. A first investigation of their physical chemical behaviour in aqueous solutions, by viscometry and fluorescence spectrometry with two complementary fluorescent probes, showed that they displayed polysoap properties which varied progressively with their chemical features, in particular the length of the alkyl side chain, the size of the spacer between the two polar amide and ammonium groups and the polymer molecular weight. Tensiometry confirmed the prevailing of the hydrophobic effect by showing that these polymers displayed a very weak activity at the water/air interface although the corresponding molecular models showed excellent tensio-active properties. Langmuir’s films were eventually obtained in the first study of this importance on cationic amphiphilic polymers. Here again, the great structural variability enabled original observations and new structure/properties relationships were obtained for the corresponding compression isotherms