Files and links (1)
Accepted (AM)Open Access (License Unspecified), Open
Journal article
Chemical optimization of macrocyclic HIV-1 inactivators for improving potency and increasing the structural diversity at the triazole ring
Organic & biomolecular chemistry, v 15(37), pp 7770-7782
2017
PMID: 28770939
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
HIV-1 entry inhibition remains an urgent need for AIDS drug discovery and development. We previously reported the discovery of cyclic peptide triazoles (cPTs) that retain the HIV-1 irreversible inactivation functions of the parent linear peptides (PTs) and have massively increased proteolytic resistance. Here, in an initial structure–activity relationship investigation, we evaluated the effects of variations in key structural and functional components of the cPT scaffold in order to produce a platform for developing next-generation cPTs. Some structural elements, including stereochemistry around the cyclization residues and Ile and Trp side chains in the gp120-binding pharmacophore, exhibited relatively low tolerance for change, reflecting the importance of these components for function. In contrast, in the pharmacophore-central triazole position, the ferrocene moiety could be successfully replaced with smaller aromatic rings, where a
p
-methyl-phenyl methylene moiety gave cPT
24
with an IC
50
value of 180 nM. Based on the observed activity of the biphenyl moiety when installed on the triazole ring (cPT
23
, IC
50
∼ 269 nM), we further developed a new on-resin synthetic method to easily access the bi-aryl system during cPT synthesis, in good yields. A thiophene-containing cPT AAR029N2 (
36
) showed enhanced entropically favored binding to Env gp120 and improved antiviral activity (IC
50
∼ 100 nM) compared to the ferrocene-containing analogue. This study thus provides a crucial expansion of chemical space in the pharmacophore to use as a starting point, along with other allowable structural changes, to guide future optimization and minimization for this important class of HIV-1 killing agents.
Metrics
Details
- Title
- Chemical optimization of macrocyclic HIV-1 inactivators for improving potency and increasing the structural diversity at the triazole ring
- Creators
- Adel A. Rashad - Drexel UniversityKriti Acharya - Drexel UniversityAnn Haftl - Drexel UniversityRachna Aneja - Drexel UniversityAlexej Dick - Drexel UniversityAndrew P. Holmes - Drexel UniversityIrwin Chaiken - Drexel University
- Publication Details
- Organic & biomolecular chemistry, v 15(37), pp 7770-7782
- Publisher
- Royal Society of Chemistry
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Chemistry
- Web of Science ID
- WOS:000412825400008
- Scopus ID
- 2-s2.0-85030244940
- Other Identifier
- 991019169787404721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Organic