jtk-303 and HIV-Infections

Bifunctional quinolinonyl DKA derivatives were first described as nonselective inhibitors of 3'-processing (3'-P) and strand transfer (ST) functions of HIV-1 integrase (IN), while 7-aminosubstituted quinolinonyl derivatives were proven IN strand transfer inhibitors (INSTIs) that also displayed activity against ribonuclease H (RNase H). In this study, we describe the design, synthesis, and biological evaluation of new quinolinonyl diketo acid (DKA) derivatives characterized by variously substituted alkylating groups on the nitrogen atom of the quinolinone ring. Removal of the second DKA branch of bifunctional DKAs, and the amino group in position 7 of quinolinone ring combined with a fine-tuning of the substituents on the benzyl group in position 1 of the quinolinone, increased selectivity for IN ST activity. In vitro, the most potent compound was 11j (IC50 = 10 nM), while the most active compounds against HIV infected cells were ester derivatives 10j and 10l. In general, the activity against RNase H was negligible, with only a few compounds active at concentrations higher than 10 μM. The binding mode of the most potent IN inhibitor 11j within the IN catalytic core domain (CCD) is described as well as its binding mode within the RNase H catalytic site to rationalize its selectivity.

Topics: Catalytic Domain; HeLa Cells; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Keto Acids; Models, Molecular; Molecular Structure; Quinolones; Ribonuclease H; RNA-Directed DNA Polymerase; Structure-Activity Relationship; Virus Replication

HIV integrase (IN) catalyzes the insertion into the genome of the infected human cell of viral DNA produced by the retrotranscription process. The discovery of raltegravir validated the existence of the IN, which is a new target in the field of anti-HIV drug research. The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported. The role played by the resistance is elucidated, as well as the possibility of bypassing this problem. New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.

Topics: Allosteric Regulation; Animals; Catalytic Domain; Drug Resistance, Viral; Enzyme Activators; Genetic Therapy; HIV; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Models, Molecular; Protein Conformation; Protein Multimerization; Virus Integration

SAR studies on the quinolone carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38.

Topics: Animals; Dogs; Haplorhini; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Microsomes, Liver; Naphthyridines; Quinolines; Rats; Structure-Activity Relationship

A series of new quinolone-3-carboxylic acids featuring a hydroxyl group at C-5 position were synthesized and evaluated for their in vitro activity against HIV in C8166 cell culture. All the compounds showed anti-HIV-1 activity with low micromolar to submicromolar EC(50) values. The most active compound 2k exhibited activity against wild-type HIV-1 with an EC(50) value of 0.13 μΜ. Preliminary structure-activity relationship of the newly synthesized quinolone analogues was also investigated. Further docking study revealed that the anti-HIV activity of these compounds might involve a two-metal chelating mechanism.

Topics: Anti-HIV Agents; Carboxylic Acids; Cell Line, Tumor; Cell Survival; HIV Infections; HIV Seropositivity; HIV-1; Humans; Models, Molecular; Quinolones; Structure-Activity Relationship

We evaluated the human immunodeficiency virus type 1 (HIV-1) integrase coding region of the pol gene for the presence of natural polymorphisms in patients during early infection (AHI) and with triple-class drug-resistant HIV-1 (MDR). We analyzed selected recombinant viruses containing patient-derived HIV-1 integrase for susceptibility to a panel of strand transfer integrase inhibitors (InSTI). A pretreatment sequence analysis of the integrase coding region was performed for 112 patients identified during acute or early infection and 15 patients with triple-class resistance. A phenotypic analysis was done on 10 recombinant viruses derived from nine patients against a panel of six diverse InSTI. Few of the polymorphisms associated with in vitro InSTI resistance were identified in the samples from newly infected individuals or those patients with MDR HIV-1. We identified polymorphisms V72I, L74I, T97A, V151I, M154I/L, E157Q, V165I, V201I, I203M, T206S, and S230N. V72I was the most common, seen in 63 (56.3%) of the AHI samples. E157Q was the only naturally occurring mutation thought to contribute to resistance to elvitegravir, raltegravir, and L-870,810. None of the patient-derived viruses demonstrated any significant decrease in susceptibility to the drugs tested. In summary, the integrase coding region contains as much natural variation as that seen in protease, but mutations associated with high-level resistance to existing InSTI are rarely, if ever, present in integrase naïve patients, especially those being used clinically. Most of the highly prevalent polymorphisms have little effect on InSTI susceptibility in the absence of specific primary mutations. Baseline testing for integrase susceptibility in InSTI-naïve patients is not currently warranted.

Topics: Adult; Amino Acid Sequence; Female; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Molecular Sequence Data; Molecular Structure; Phylogeny; Polymerase Chain Reaction; Polymorphism, Genetic