Synthesis And Structure-Activity Relationship Of Peptidic HTLV-I Protease Inhibitors

A large number of diseases including adult T-cell leukemia(ATL) and tropical spastic paraparesis/HTLV-I-associated myelopathy(TSP/HAM) are caused by the human T-cell leukemia virus typeâ… (HTLV-I).HTLV-I infection is currently considered as an intractable disease because 20-30 million individuals worldwide are viral carriers.HTLV-I protease is responsible for the proliferation of the retrovirus and then becomes an attractive target for developing inhibitors against HTLV-I infections.Substrates containing natural amino acid residues are easily digested by proteases. When a non-natural amino acid,(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid(Apns), containing a hydroxymethylcarbonyl(HMC) isostere,that can mimic the tetrahedral transition-state of amino bond hydrolysis but cannot itself be hydrolyzed by the enzyme,is introduced,the protease's pharmacological actions are suspended.Using KNI-10455 as a reference compound(IC₅₀=140 nM),we were interested in modifying the N-and C-terminals and truncation studies to enhance HTLV-I protease inhibition.Sixty-six peptidic compounds containing Apns were prepared by solution phase peptide synthesis.Fifty-three of them were tetrapeptidic inhibitors.Nine of them were tripeptidic compounds.Four of them were dipeptidic inhibitors.The structures were identified by ¹H-NMR and MS spectra.All novel compounds were evaluated for HTLV-I and HIV-1 protease assays. Fifty-three tetrapeptides exhibited high HIV-1 protease inhibition at 50nM(＞97%).Forty-two tetrapeptides showed potent HTLV-I protease activity(IC₅₀＜137nM) that were greater than the reference compound.None of the tri-and di-peptides efficiently inhibited HTLV-I protease at 600 nM(＜14%).The most potent HTLV-I protease inhibitor was(R)-N-(2,2-dimethyl) propyl-3-{{(2S,3S)-3-{(2S)-2-[(2S)-2-butyrylamino-2-phenyl]acetylamino-3,3-dimethyl}butan oylamino-2-hydroxy-4-phenyl}}butanoyl-5,5-dimethyl-l,3-thiazolidine-4-carboxamide(IC₅₀= 74nM).