HIV-1 fusion inhibitors targeting the membrane-proximal external region of Env spikes.

Nature Chemical Biology
Tianshu XiaoBing Chen

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.

References

Jan 20, 1995·Science·T Clackson, J A Wells
Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
May 22, 1997·Nature·W WeissenhornD C Wiley
Jun 18, 1998·Cell·D C Chan, P S Kim
Jun 6, 2000·Journal of Biomolecular Screening·J H ZhangK R Oldenburg
Feb 5, 2003·Journal of Magnetic Resonance·Charles D SchwietersG Marius Clore
May 2, 2003·Nature Biotechnology·Debra Robertson
May 30, 2003·The New England Journal of Medicine·J Michael Kilby, Joseph J Eron
Nov 16, 2005·Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology·Eva PovedaVincent Soriano
Sep 12, 2006·Bioorganic & Medicinal Chemistry·Chandima AbeywickramaArthur David Baker
Sep 12, 2006·Proceedings of the National Academy of Sciences of the United States of America·Gary FreyStephen C Harrison
Oct 4, 2006·Nature Reviews. Drug Discovery·Peter ImmingAchim Meyer
Dec 2, 2006·Nature Reviews. Drug Discovery·John P OveringtonAndrew L Hopkins
Feb 28, 2008·The Journal of Biological Chemistry·Yuxian HeLinqi Zhang
Mar 7, 2008·Proceedings of the National Academy of Sciences of the United States of America·Gary FreyBing Chen
Nov 21, 2008·Methods in Molecular Biology·David C Montefiori
Oct 28, 2009·Antimicrobial Agents and Chemotherapy·Dong XieHe Jiang
Aug 31, 2010·Bioorganic & Medicinal Chemistry Letters·Olivier BergerYen Vo-Hoang
Aug 4, 2011·Archives of Pharmacal Research·Matthew GrantByungse Suh
Nov 15, 2011·Nucleic Acids Research·Irina KufarevaRuben Abagyan
Jul 10, 2012·Proceedings of the National Academy of Sciences of the United States of America·James M KovacsBing Chen
Jul 1, 1995·Journal of Biomolecular NMR·C BartelsK Wüthrich
Nov 2, 2013·Science·Jean-Philippe JulienIan A Wilson
Dec 3, 2013·Journal of Immunological Methods·Marcella Sarzotti-KelsoeDavid C Montefiori
Oct 9, 2014·Nature·Marie PanceraPeter D Kwong
May 23, 2015·Nature Reviews. Cancer·George J Weiner
Jun 25, 2016·Science·Jyoti DevJames J Chou
Dec 3, 2016·Nature Reviews. Drug Discovery·Rita SantosJohn P Overington

❮ Previous
Next ❯

Citations

Apr 24, 2020·Nature Chemical Biology·Shan Su, Shibo Jiang
Jul 2, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Qingxin Li, CongBao Kang
Oct 6, 2020·Expert Opinion on Therapeutic Patents·Tiziana Ginex, F Javier Luque
Dec 11, 2020·Journal of Cellular and Molecular Medicine·Yanting DingBing Niu
Jan 28, 2021·Microorganisms·Jean-François BruxelleRalph Pantophlet
Feb 13, 2021·Biochemical Pharmacology·Christian Bailly
Apr 2, 2021·Journal of Immunological Methods·Peter CanningTerry Rabbitts
May 1, 2021·Viruses·Tianshu XiaoBing Chen
Aug 9, 2021·International Journal of Biological Macromolecules·Yunxia XuWei Xu
Jul 2, 2021·Annual Review of Virology·Han-Yuan Liu, Priscilla L Yang

❮ Previous
Next ❯

Methods Mentioned

BETA
surface plasmon resonance
NMR
gel-filtration
gel filtration
transfection
chips

Software Mentioned

SPARKY
MPER
XPLOR
NMRpipe
MestReNova
NIH
Excel STDEV
GraphPad Prism
FACSDIVA
BiaEvaluation

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.