Targeting the Dimerization Interface of HIV-1 Protease:  Inhibition with Cross-Linked Interfacial Peptides

Abstract

Agents have been designed and synthesized which target the dimerization interface of HIV-1 protease. These agents, which contain cross-linked peptides from the N- and C-termini of the protease, both inhibit HIV-1 protease activity and decrease the amount of protease dimer in solution as measured by size exclusion chromatography, protein crosslinking, and protease fluorescence studies. Additionally we have shown that active site-targeted agents inhibit HIV-1 protease activity but have little effect on protease dimerization. These data support the claim that inhibition with the crosslinked agents is based on a decrease in the amount of protease homodimer in solution which in turn is responsible for a decrease in the activity of the protease.

Kinetic and Thermodynamic Analysis of Dimerization Inhibitors Binding to HIV Protease Monomers by Surface Plasmon Resonance

“…Были созданы ингибиторы димеризации пВИЧ, взаимодействующие с интерфейсом димеризации пВИЧ и блокирующие ассоциацию мономеров в димер и/или разрушающие активный димер пВИЧ [10,11]. Недавно были найдены еще несколько пептидных [12][13][14] и непептидных [15,16] ингибиторов димеризации пВИЧ, отличающиеся кинетическими профилями взаимодействия с пВИЧ. Однако разработка более эффективных ингибиторов димеризации тормозится недостатком термодинамических данных о балансе сил взаимодействия таких ингибиторов с мономерами пВИЧ.…”

Selective disruption of protein aggregation by cyclodextrin dimers

“…A decrease in cross-linking efficiency by reagents such as bis(sulfosuccinimidyl)suberate (BS) has been used to demonstrate the dissociation of protein dimers (19,20). We saw (Fig.…”

Targeting protein–protein interactions by rational design: mimicry of protein surfaces

“…Elaborating on this innovative research, Chmielewski and colleagues designed inhibitors intended to mimic the four interdigitating strands that form the dimerization interface by cross-linking N-terminus and C-terminus-derived peptides (Zutshi et al 1997 (Sheng & Sala 2001). Implicated in a number of associations with medicinally important proteins, the design of inhibitors of PDZ domains may lead to the treatment of diseases, such as metastatic breast cancer (Koo et al 2002), prostate cancer (Chaib et al 2001) and Parkinson's disease (Dev et al 2003).…”