Twelve drugs, collectively calledstatins, have been developed as competitive
inhibitors of this enzyme and approved for therapeutic use. They have proved to be
very effective in producing a substantial reduction in plasma cholesterol so that
statins are currently the most widely used drugs in the developed world. However,
they are associated with a number of side effects such as muscle cramps and disturb-
ance of liver enzymes and less commonly acute renal failure. Some statins are known
to damage mitochondria and this may underlie some of these side effects.
One obvious target for a new candidate drug is HDL, the aim being to increase its
plasma levels and hence facilitate increased reverse cholesterol transport. Some
Japanese individuals have raised HDL due to a genetic deficiency of the enzyme
cholesteryl ester transfer protein (CETP) (Table 6.4), and this led to the development
of CETP inhibitors. One such candidate drug, torcetapib, was developed but had to be
withdrawn from Phase III clinical trials (Section 18.3.2) because although it increased
serum HDL it resulted in an increased death rate. Whether or not this is a general
property of all CETP inhibitors or indeed of all agents that raise HDL, or one specific to
torcetapib, remains to be investigated. Two transporter proteins, ABCG1 and ABCA1,
located on cell membranes have been shown to promote the efflux of cholesterol from
macrophages to form nascent HDL and hence to stimulate reverse cholesterol trans-
port. The genes encoding these two transporters are stimulated by liver X receptors
(LXR) that are nuclear transcription factor receptors, and agonists of this receptor
have been shown to increase HDL cholesterol by 48% and to improve atherosclerosis
in animals. Some of these agonists are now in human clinical trials. Other research has
indicated that raising the amount of apoA-1 in HDL could be beneficial provided they
do not modify its structure and some novel candidate drugs that may increase apoA-1
are currently in development. Recent research has also indicated that the protein
proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the
regulation of the LDL receptor. Claims have been made that the use of iRNA to silence
the gene for PCSK9 in mice reduces plasma cholesterol levels by half. Whether or not
this approach can be applied to humans remains to be seen.Case study Target selection: HIV/AIDS therapy
These conditions are induced by the human immunodeficiency viruses HIV-1 and
HIV-2 that were discovered in 1983 and 1985 respectively. HIV-1 is the most virulent
and most prevalent in the worldwide pandemic: 33 million people worldwide are
believed to be living with HIV. They are retroviruses and have a RNA genome. They
attack the immune system, especially T-helper cells, resulting in an increased rate of
cell apoptosis and death. The virus attacks these cells via attachment of the viral
envelope glycoprotein gp120 to a CD4 receptor on the host cell. Membrane penetra-
tion by the virus requires the additional involvement of either one of two cytokine
co-receptors CCR5 and CXCR4 on the surface of the patient’s cells that are linked to
GPCRs. Once attached to the CD4 and the co-receptor, the envelope protein undergoes
a conformational change that allows penetration into the host cell. The virus then
injects various enzymes including a reverse transcriptase, protease, integrase and
RNase into the cell. The reverse transcriptase promotes the synthesis of a DNA copy722 Drug discovery and development