Inhibiting HTLV-1 Protease: A Viable Antiviral Target

Abstract

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that can cause severe paralytic neurologic disease and immune disorders as well as cancer. An estimated 20 million people worldwide are infected with HTLV-1, with prevalence reaching 30% in some parts of the world. In stark contrast to HIV-1, no direct acting antivirals (DAAs) exist against HTLV-1. The aspartyl protease of HTLV-1 is a dimer similar to that of HIV-1 and processes the viral polyprotein to permit viral maturation. We report that the FDA-approved HIV-1 protease inhibitor darunavir (DRV) inhibits the enzyme with 0.8 μM potency and provides a scaffold for drug design against HTLV-1. Analogs of DRV that we designed and synthesized achieved submicromolar inhibition against HTLV-1 protease and inhibited Gag processing in viral maturation assays and in a chronically HTLV-1 infected cell line. Cocrystal structures of these inhibitors with HTLV-1 protease highlight opportunities for future inhibitor design. Our results show promise toward developing highly potent HTLV-1 protease inhibitors as therapeutic agents against HTLV-1 infections.

Viral proteases: Structure, mechanism and inhibition

“…3 G). UM6 and PU6 were also effective at inhibiting Gag processing in biochemical assays and maturation of virus-like particles [67] . The cocrystal structures of DRV and analogs bound to HTLV-1 protease provide a promising path toward designing potent HTLV-1 protease inhibitors as therapeutics.…”

“…However, the larger HTLV-1 protease active site prevented optimal packing with the flap residues. DRV, a picomolar inhibitor of the HIV-1 protease, has a K i of about 1 μM against the HTLV-1 protease [67] . Cocrystal structures of DRV bound to HIV-1 and HTLV-1 proteases revealed a similar binding mode.…”

Different Enzyme Conformations Induce Different Mechanistic Traits in HIV‐1 Protease

“…They also expanded the understanding of aspartic proteases, something that can have implications in the studies of other retroviruses such as the human T-cell lymphotropic virus type 1 (HTLV-1), and on future endeavours on drug design campaigns. [18]…”

“…The results highlighted technical aspects that are broadly applicable in the study of enzyme reaction mechanisms with hybrid QM/MM approaches, and underlined important features of the catalysis by HIV‐1 PR. They also expanded the understanding of aspartic proteases, something that can have implications in the studies of other retroviruses such as the human T‐cell lymphotropic virus type 1 (HTLV‐1), and on future endeavours on drug design campaigns [18] …”

Kinetics of Bovine leukemia virus aspartic protease reveals its dimerization and conformational change

“…In fact, the PR of Human immunodeficency virus (HIV) is one of the main targets of antiretroviral drugs, and several inhibitors are currently used in the antiviral pharmacological treatment [13,15,16]. On the other hand, until now there are no direct-acting antivirals against HTLV targeting HTLV-PR, however, recent works demonstrate that there is active interest in the search and study of new HTLV-PR inhibitors [17,18]. The main substrate of PR is Gag, a precursor polyprotein relevant for capsid self-assembling.…”