HIV-1 fusion inhibitors targeting the membrane-proximal external region of Env spikes.
Nat Chem Biol
; 16(5): 529-537, 2020 05.
Article
in En
| MEDLINE
| ID: mdl-32152540
ABSTRACT
Combination antiretroviral therapy has transformed HIV-1 infection, once a fatal illness, into a manageable chronic condition. Drug resistance, severe side effects and treatment noncompliance bring challenges to combination antiretroviral therapy implementation in clinical settings and indicate the need for additional molecular targets. Here, we have identified several small-molecule fusion inhibitors, guided by a neutralizing antibody, against an extensively studied vaccine target-the membrane proximal external region (MPER) of the HIV-1 envelope spike. These compounds specifically inhibit the HIV-1 envelope-mediated membrane fusion by blocking CD4-induced conformational changes. An NMR structure of one compound complexed with a trimeric MPER construct reveals that the compound partially inserts into a hydrophobic pocket formed exclusively by the MPER residues, thereby stabilizing its prefusion conformation. These results suggest that the MPER is a potential therapeutic target for developing fusion inhibitors and that strategies employing an antibody-guided search for novel therapeutics may be applied to other human diseases.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
HIV Envelope Protein gp41
/
Anti-HIV Agents
/
Virus Internalization
Limits:
Humans
Language:
En
Journal:
Nat Chem Biol
Journal subject:
BIOLOGIA
/
QUIMICA
Year:
2020
Document type:
Article
Affiliation country: