Brain Delivery of HIV Protease Inhibitors

Abstract

To overcome the problems of peptidomimetic drug delivery to the specific organs, the use of dihydropyridine <--> pyridinium chemical delivery systems to deliver peptides to the brain is considered in this work. An HIV protease inhibitor lead compound; KNI 279 was selected for the study. The N-alkylated dihydroisoquinoline derivatives of KNI-279 were synthesized and tested for their ability to be oxidized by brain homogenate and showed good results with reasonable half-life times specially for the N-alkoxycarbonyl-methyl derivative 8. The in-vivo distribution of compound 8 proved the brain delivery and locked in property of HIV PR inhibitors in the brain. All the prepared compounds (both quaternary and dihydro derivatives) showed between 51 and 86 % HIV PR inhibitory activity compared to the parent compound.

What is Hidden Behind Peptide Bond Restriction and &#945;-Carbon Asymmetry of Conserved Antigens? Peptide Bond Isosters and Chirally Transformed Pseudopeptides as Novel Elements for Synthetic Vaccines and Therapeutic Agents Against Malaria

“…The first reported substrate analogue design studies revealed that hepta peptide [41][42][43], reduced bond isosters L-Y-[CH 2 -NH]-L-P and L-F-[CH 2 -NH]-L-P inhibited HIV PR-catalysed hydrolysis of related all-L peptide (Ac-SQNYPVV-NH 2 ) with K i values 10 3 times lower than K m value for the substrate. Subsequent studies comparing various isosters with identical flanking peptide sequences indicated that the reduced amide isoster was the least effective of those tested.…”

“…Antibodies raised against the modified reduced amide epitope were specifically able to recognise those native antigen's structural features which could not be mimicked by the natural all-L amino acids peptide (MSP-1 [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] ). These findings have revealed that receptors on RBC for the MSP-1 42-61 epitope are fairly selective for L-natural conformations on amino acid ligands which (as shown) can be mimicked by specific -[CH 2 -NH] modifications; so, inducing modulated molecular [CH 2 -NH] surrogate antibodies can differentiate topochemistry but not chirality.…”

Further Insight into the Mechanism of the Novel Multicomponent Reactions Involving Isoquinoline and Dimethyl Acetylenedicarboxylate in the Presence of 3-Methylindole: Theoretical and Experimental Approach

“…Isoquinoline skeletons are seen within a large number of naturally occurring, biologically active, synthetic heterocyclic compounds , including such drugs as papaverine . Moreover, 1,2‐dihydroisoquinoline derivatives act as delivery systems that transport drugs through the otherwise highly impermeable blood–brain barrier and exhibit sedative , antidepressant , antitumor, and antimicrobial activities .…”

TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs

“…In addition, most of the FDA-approved PIs are known substrates of the human multidrug-resistance gene (MDR1) transporter, P-glycoprotein (P-gp), which limits their transport across the BBB to the CNS [6]. Approaches such as developing potent PI derivatives [7], prodrugs (e.g., azidothymidine [8, 29] or using P-gp inhibitors [10] have been investigated to enhance the CNS bioavailability of anti-HIV drugs. However, developing new drugs or prodrugs could be an extensive undertaking with uncertain future.…”