HIV-1 CA
August 2023
HIV-1 capsid protein (CA)
HIV-1 capsid protein (CA) composes the core of the virus particles (capsid) of the human immunodeficiency virus type 1 (HIV-1) - the one responsible for causing AIDS (Acquired Immunodeficiency Syndrome). (keep reading for bonus at the end)
Even if several life-saving treatments have been developed, most require taking pills daily, which often causes suboptimal adherence to the therapy. This leads to negative treatment outcomes and the emergence of drug-resistant HIV-1 variants. Therefore, the development of new long-acting medications that require less frequent administrations could provide more efficient treatment options.
HIV-1 CA has recently emerged as a therapeutic target for long-acting small-molecule drugs. The HIV-1 capsid is assembled thanks to interactions between multiple HIV-1 CA units. Since the integrity of the capsid is essential for the infectivity of the virus, targeting the interactions that hold it together is an attractive therapeutic strategy.
Some small-molecule antiretroviral drugs with this mechanism of action have been studied and developed, and in December 2022, lenacapavir (by Gilead Sciences) was approved as a first-in-class by the FDA. The therapy with this molecule only requires a twice-yearly treatment, thanks to its high potency and metabolic stability.
The HIV-1 capsid shell comprises roughly 1500 HIV-1 CA protein units, which form extensive protein-protein interfaces that small molecules could target. The 3D crystal structure of the lenacapavir:HIV-1 CA complex showed the drug at the interface between capsid protein monomers (Image 1A). The binding site is located between the N-terminal domain of one subunit of the CA (NTD) and the C-terminal domain (CTD) of an adjacent protein subunit. Lenacapavir forms extensive hydrophobic and electrostatic interactions with the two HIV-1 CA molecules. The sulfonamide group is crucial for activity because it is involved in an interaction network that bridges NTD residue N74 to CTD residue N183 (Image 1B).
Image 1. A: Binding site at the interface between two adjacent HIV-1 CA units (in aquamarine one HIV-1 CA unit, in purple the adjacent molecule, PDB: 6V2F). The electron density map (2Fo-Fc) at this interface indicates the presence of the lenacapavir at this location (in pink). The CTD and NTD are indicated. The molecular surface was produced with the 3decision® software. B: The interaction network of lenacapavir, with a focus on the sulphonamide moiety (in the circle), bridging the residues N74 on the NTD and N183 on the CTD. Protein-ligand contacts were calculated with the 3decision® software.
Interestingly, previous structural studies on HIV-1 CA shows that this binding site is also targeted by two cellular cofactors crucial for HIV-1 infection: nucleoporin 153 (NUP153), and cleavage and polyadenylation specificity factor 6 (CPSF6). These are nuclear pore components that facilitate nuclear entry. Comparing the three crystal structures of the HIV-1 CA in complex with lenacapavir, NUP153, and CPSF6, the ligand overlays very well with both peptides (Image 2), indicating that it can directly compete with these cofactors. This structural finding was supported by biochemical data showing that lenacapavir prevents viral cDNA's nuclear import.
Image 2. Overlay of HIV-1 CA in complex with: lenacapavir (ligand in pink, protein in dark orange, PDB: 6V2F), NUP153 (in white, 4U0D) and CPSF6 (in blue, 4U0B). The picture is produced using the highlight mode of 3decision® software, which only shows different parts of the compared proteins. The orange helix is from the structure in the complex with lenacapavir, which is shifted in position compared to the helixes of the structures in complex with the co-factors.
In this study, the structural insights provided the rationale for the therapeutic action of the drug lenacapavir that could be exploited to develop other molecules with similar mechanisms.
Bonus: electron density maps overlap
In a recent paper, a new long-acting inhibitor targeting the HIV-1 capsid (GSK878) has been reported and structurally characterized. With 3decision®, you can easily spot differences in the electron densities of the structures of HIV-1 CA in complex with lenacapavir and with GSK878.
Reference:
Link JO, Rhee MS, Tse WC, Zheng J, Somoza JR, Rowe W, Begley R, Chiu A, Mulato A, Hansen D, Singer E, Tsai LK, Bam RA, Chou CH, Canales E, Brizgys G, Zhang JR, Li J, Graupe M, Morganelli P, Liu Q, Wu Q, Halcomb RL, Saito RD, Schroeder SD, Lazerwith SE, Bondy S, Jin D, Hung M, Novikov N, Liu X, Villaseñor AG, Cannizzaro CE, Hu EY, Anderson RL, Appleby TC, Lu B, Mwangi J, Liclican A, Niedziela-Majka A, Papalia GA, Wong MH, Leavitt SA, Xu Y, Koditek D, Stepan GJ, Yu H, Pagratis N, Clancy S, Ahmadyar S, Cai TZ, Sellers S, Wolckenhauer SA, Ling J, Callebaut C, Margot N, Ram RR, Liu YP, Hyland R, Sinclair GI, Ruane PJ, Crofoot GE, McDonald CK, Brainard DM, Lad L, Swaminathan S, Sundquist WI, Sakowicz R, Chester AE, Lee WE, Daar ES, Yant SR, Cihlar T. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020 Aug;584(7822):614-618. doi: 10.1038/s41586-020-2443-1. Epub 2020 Jul 1. PMID: 32612233; PMCID: PMC8188729.