HTLV-1, like other retroviruses, encodes an aspartic
PR that processes viral Gag and Gag-(Pro)-Pol polyproteins during maturation. The PR
has two aspartic acid residues in its active site that participate in the
hydrolysis of peptides through an acid-base
mechanism. Similar to the HIV-1 PR, the function of the HTLV-1 PR is critical
for virus replication. Several PR inhibitors are in clinical use for the treatment of acquired immune deficiency
syndrome (AIDS). Based on the success of the PR inhibitors for anti-HIV-1
therapy, the PR of HTLV-1 is also a
promising drug target for the discovery of novel anti-HTLV-1 drugs. HIV-1 PR inhibitors, i.e., saquinavir, indinavir, nelfinavir, atazanavir, darunavir,
ritonavir and lopinavir possess a hydroxyl ethylamine or a hydroxyl ethylene
moiety that act as transition state analogues.
Since 3D structure of HTLV-I PR is similar R1 to
HIV-1 PR 51-52, potent HIV-1 PR inhibitors,
such as compounds KNI-727, KNI-764, and ritonavir were tested as HTLV-1 inhibitors . Unfortunately, these compounds
were ineffective against HTLV-I PR, however, other KNI compounds were active
(Table 2). Ritonavir displayed an anti-leukemic activity
against ATL cells ex vivo 53. However, this was mainly due to inhibition of NF-?B activation, rather than inhibition of the
HTLV-1 PR 54.
Unlike HIV-1 PR, for which hundreds of crystal
structures have been released, only a few
structures of HTLV-1 PR are published R2 to date (11 Structures). Comparison of the crystal
structures of HTLV-1 and HIV-1 PRs revealed that they have very similar folds. Both enzymes are homodimeric
aspartyl proteases and only share a 28% sequence identity and a 45% similar
sequence identity at the substrate binding sites. The HIV-1 PR coding sequence has only 98 amino acids per
chain, whereas the HTLV-1 PR is substantially longer with 125
residues in each chain.
Recently, the crystal structure of HTLV-1 PRs in complex with HIV-1
indinavir (IDV) is
also resolved (Protein
data bank code 3WSJ) 51.
The investigation of HTLV-1
PR inhibitors is at an early stage. Studies indicated that the HIV-1 PR inhibitors currently used in AIDS
therapy are not able to inhibit HTLV-1 PR potently. Probably,
differences in the amino acid sequences of the HIV-1 and HTLV-I PRs result in
differences in susceptibilities to inhibitorsR3 .
Table 1 summarizes inhibitors of HTLV-1 PR having Ki (or IC50)
values of less than 500 nM; these compounds can be
considered leads for further investigations. Except for the MES13-099 and DMP-323, the compounds are
peptides or modified peptides. JG-365, a heptapeptide inhibitor, is the best
inhibitor of HTLV-1 PR reported to date with a Ki of 6 nM. The
structures of JG-365 55 is provided in Figure 2.