Potent Human Immunodeficiency Virus Type 1 Protease Inhibitors That Utilize Noncoded d-Amino Acids as P₂/P₃ Ligands

Abstract

Noncoded D-amino acids have been designed to replace the quinaldic amide-asparaginyl moiety (P2/P3 ligand) found in several potent human immunodeficiency virus (HIV) protease inhibitors such as LY289612. The substituted nitrogen, optimally an N-methanesulfonyl moiety, served as a CH2CONH2 (asparagine side chain mimic), while the amino acid side chain became the backbone and P3 ligand of these novel inhibitors. Compounds derived from S-aryl-D-cysteine proved to be potent HIV protease inhibitors which also exhibited potent whole cell antiviral activity. Oxidation of the cysteines to the sulfoxide or sulfone oxidation states resulted in significant improvements in potency. For example, the compound derived from N-(methyl-sulfonyl)-2-S-naphthylcysteine sulfone, 17c, was a 3.5 nM inhibitor of HIV protease which inhibited the spread of virus in MT4 cells with an IC50 = 4.3 nM. Compounds 17c,g,i were found to be orally bioavailable in a rat model.

Mechanistic Understanding of Lanthipeptide Biosynthetic Enzymes

“…367,412−416 This unusual stereochemistry is thought to contribute to proteolytic stability, 87,417−419 structural conformation, 420 and bioactivity. 413,414,421 As only L-amino acids are genetically encoded, access to the D stereochemistry requires post-translational modification and several unique mechanisms for this transformation have been uncovered.…”

Approaches to the Design of Effective HIV-1 Protease Inhibitors

“…A non natural D amino acid can replace a natural L amino acid [61]. For example, in order to keep the affinity of compound LY289612 9 (IC 50 =1.5 nM) towards HIV-1 PR while enhancing its Difluoroketones Several nanomolar inhibitors containing difluoroketone [53][54][55] Boc=butoxycarbonyl pharmacokinetic profile, a distant analogue of Dcysteine 12 was inserted that was meant to interact with the S 2 subsite of the enzyme active site [52,62].…”

“…Only a few potent inhibitors are based on this bioisostere.The problem with many large HIV-1 PR inhibitors is that the liver tends to clear them quickly from circulation. The molecular weight distribution of all marketed oral and systemic drugs shows a maximum in the bell-shaped curve around 350 daltons and a tail[56][57][58] bioisosteres were proposed, in which hydration of the central fluorinated ketone moiety generates mimics of the tetrahedral intermediate.Numerous HIV-1 PR hydroxyethylene inhibitors are based on the Phe*Pro cleavage site, as illustrated by LY289612 9 and L-685,434 10, the hydroxyethylene precursors of marketed inhibitors nelfinavir and indinavir[37,51,52].The clinical progression of MDL 74,695 series may however be hampered by its poor bioavailability and its…”

Discovery and Characterization of Bicereucin, an Unusual d-Amino Acid-Containing Mixed Two-Component Lantibiotic

“…Introduction of d -amino acids into ribosomally synthesized peptides is highly valuable since such residues reduce susceptibility to proteolysis. 30 A limited number of enzymes have been reported that post-translationally introduce d - stereocenters into peptides, 31 − 33 but they have not yet been used for synthetic purposes. We investigated the utility of LanJ enzymes to prepare d -amino acid containing natural products.…”