Maturation inhibitors
Maturation inhibitors represent a promising class of investigational antiviral drugs designed to combat human immunodeficiency virus (HIV) during its final stage of viral development. These inhibitors target the maturation process of the virus, which is crucial for the production of infectious viral particles. The first maturation inhibitor, bevirimat, entered phase-two clinical studies in 2010 and was initially aimed at treatment-naïve individuals. However, challenges arose due to high levels of resistance observed in early trials, prompting the development of additional inhibitors that could better withstand such resistance.
Maturation inhibitors, including bevirimat and another compound, vivecon, are typically administered once daily, which may enhance adherence to treatment regimens, particularly for those who have previously faced complex dosing schedules. They are generally well-tolerated with few reported side effects. The introduction of this drug class could offer new therapeutic options for individuals with resistant HIV infections, potentially improving treatment outcomes by lowering viral loads. Despite promising advancements, further research and development in this area have faced hurdles, including setbacks with ongoing studies.
Maturation inhibitors
Definition
Maturation inhibitors make up a newer, investigational, antiviral drug class that attacks the human immunodeficiency virus (HIV), a retrovirus, in the last stage of development. This attacks prevents the continued retroviral infection of the body’s T cells.
Patient Population and Planned Use
The first-in-class maturation inhibitor, bevirimat (also known as PA-457), reached phase-two clinical studies in 2010, but the population being considered for treatment expanded as quickly as research on bevirimat progressed. Maturation inhibitors were initially considered for people infected with HIV who were treatment naïve, that is, had not previously taken this or any other medication for HIV. However, the surprising and high levels of resistance to bevirimat in early studies led researchers to begin developing additional maturation inhibitors that could withstand initial resistance instead. Resistance to bevirimat appeared linked to resistance that developed in people who had used protease inhibitors, which work on a similar area of HIV as maturation inhibitors. Most studied maturation inhibitors, including the lead compound bevirimat and vivecon (also known as MPC-9055), a maturation inhibitor in earlier clinical studies, are given once daily.
Mechanism of Action
Maturation inhibitors block viral replication of HIV, a retrovirus, at viral maturation, the final stage of virus production before budding, when the infectious cell spreads through the body. During maturation, proteins gather and are released from cells to spread to other T cells in the body. Unlike protease inhibitors, which target protease enzymes at this viral stage, the target of maturation inhibitors is in the Gag (group-specific antigen) region of the HIV cell. To keep the virus noninfectious, maturation inhibitors work at the polyprotein precursor, the primary protein that assembles the virions into mature particles that can be sent to infect other cells.
Advantages
Maturation inhibitors have many theoretical and actual advantages compared with existing treatment options for persons with HIV, whether these persons are treatment naïve or treatment experienced. The pharmacokinetics of maturation inhibitors, such as bevirimat, allow for once-daily dosing. This feature alone greatly increases adherence, especially in treatment-experienced persons who typically have undergone difficult and complicated dosing regimens. Maturation inhibitors as a class are generally easy to tolerate, with few side effects and drug interactions noted. The goal of treatment with maturation inhibitors is to add a new drug class to existing options for highly active antiretroviral therapy (HAART) of HIV, so as to provide new and successful treatment options for people with resistant disease.
Impact
The addition of a new antiretroviral class can reinvigorate treatment of resistance disease and can contribute to successful adherence with easier dosing schedules and a good side effect profile, which improve the adherence potential of drugs in this class. The development of bevirimat provided a new opportunity for treatment-resistant persons to lower their viral loads. Phase-two studies of bevirimat, however, identified a greatly reduced effect in persons who were resistant to protease inhibitors, possibly because protease inhibitor activity altered the Gag area of HIV to render bevirimat inactive. Drug manufacturers continued to experiment with other investigational compounds in the maturation inhibitor class, such as MPC-9055, but in 2010, these studies were placed on hold.
Bibliography
Martin, David E., Karl Salzwedel, and Graham P. Allaway. “Bevirimat: A Novel Maturation Inhibitor for the Treatment of HIV-1 Infection.” Antiviral Chemistry and Chemotherapy 19, no. 3 (2008): 107-113.
Salzwedel, Karl, David E. Martin, and Michael Sakalian. “Maturation Inhibitors: A New TherapeuticClass Targets the Virus Structure.” AIDS Review 9, no. 3(2007): 162-172.
Sarkar, Sucharita, et al. "Structural Basis of HIV-1 Maturation Inhibitor Binding and Activity." Nature Communications, 4 Mar. 2023, doi.org/10.1038/s41467-023-36569-y. Accessed 4 Feb. 2025.
Wit, Ferdinand W. N. M., Joep M. A. Lange, and Paul A. Volberding. “New Drug Development: The Need for New Antiretroviral Agents.” In Global HIV/AIDS Medicine, edited by Paul A. Volberding et al. Philadelphia: Saunders/Elsevier, 2008.