Journal
FASEB JOURNAL
Volume 26, Issue 3, Pages 1018-1026Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.11-195289
Keywords
peptide; gp41; TLT; T20; T1144
Categories
Funding
- U.S. National Institutes of Health [AI046221]
- National Natural Science Foundation of China [81072581, 81173098]
- National Science and Technology Major Project of Original New Drug Research Key Technology grant [2009ZX09301-002]
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We previously reported that the combinatorial use of T20 and T1144, the first and next generations of HIV fusion inhibitors, containing different functional domains resulted in synergistic anti-HIV-1 effect, but this effect diminished when T20 and T1144 were covalently linked together. To elucidate the mechanism underlying this synergistic anti-HIV-1 effect, we studied the interactions between T20 and T1144 either in a mixture state or in a covalently linked state. T20 alone in solution was largely featureless, while T1144 alone was in alpha-helical trimeric conformation. When mixed in solution, T20 and T1144 showed a loose and transient interaction, with a moderate 10% alpha-helical content increase, but this interaction was greatly enhanced in the linked state, and T20 and T1144 showed similar to 100% alpha-helical content. These results suggested that the loose and transient interaction between T20 and T1144 may destabilize the T1144 trimer, which makes its otherwise shielded binding sites more accessible to N-terminal heptad repeat (NHR) and increases its associating rate, thus increasing its anti-HIV-1 potency against the temporarily exposed target in NHR and causing the synergistic anti-HIV-1 effect. However, the strong interaction between T20 and T1144 in the covalently linked state may shield their NHR-binding sites, resulting in reduction of the synergistic effect.-Cai, L., Pan, C., Xu, L., Shui, Y., Liu, K., Jiang, S. Interactions between different generation HIV-1 fusion inhibitors and the putative mechanism underlying the synergistic anti-HIV-1 ef-fect resulting from their combination. FASEB J. 26, 1018 -1026 (2012). www.fasebj.org
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